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Genetic disorders > Genetic Disorders > Flashcards

Genetic Disorders Flashcards

1
Q

What are the features of Joubert syndrome

A

Classic features

  • Abnormal brain (molar tooth sign)
  • Hypotonia
  • Developmental delays
  • Ataxia
  • Episodic tachypnea (rapid breathing), apnea
  • Atypical eye movement (nystagmus, oculomotor apraxia)
  • Speech apraxia
  • Abnormal EEG, seizures
  • Autism, behavior issues, variable cognitive impairment
  • Obesity
  • Scoliosis
  • Isolated growth hormone deficiency, thyroid hormone deficiency
  • Conductive hearing loss
  • Tongue hypertrophy
  • Situs inversus
  • Long face, bitemporal narrowing, high-arched eyebrows, ptosis, prominent nasal bridge, triangle-shaped mouth, prognathism, low-set ears

Other types may also include

  • Ocular defect (such as leber congenital amaurosis)
  • Renal defect (including cystic kidney disease)
  • Renal and ocular, with possible congenital hepatic fibrosis
  • Hepatic defect (congenial hepatic fibrosis)
    • Also see colobomas and nephronophthisis
  • Orofacialdigital defect (tongue hamartomas, oral frenulae, polydactyly, cleft lip/palate)
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2
Q

How is Joubert syndrome inherited?

A

Autosomal recessive, x-linked recessive, or digenic

21 genes associated

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3
Q

What are the critical genes for 15q11.2 deletion syndrome?

A

CYFIP1, NIPA2, NIPA1

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4
Q

What are the features of 15q11.2 deletion syndrome?

A
  • Physical features (may or may not be present)
    • Broad forehead
    • Hypertelorism
    • Slender fingers
  • Features
    • Congenital heart defect
    • Hypotonia
    • Developmental & speech delay
    • Intellectual disability
    • Seizures
    • Dyspraxia
    • Ataxia
    • Sleep disorders
    • Autism spectrum disorder
    • Happy demeanor
    • OCD, ADHD
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5
Q

What are the features of 15q13.3 deletion syndrome?

A

Features (HIGHLY VARIABLE, MAY HAVE NO FEATURES)

  • Associated with autism spectrum disorders
  • Associated with psychiatric disorders (Schizophrenia and bipolar)
  • Intellectual disability
  • Speech delays
  • Seizures
  • Cardiac defects
  • Hyperactivity, poor attention span, mood disorder, impulsive/aggressive behavior
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6
Q

What are the features of 16p11.2 deletion/duplication syndrome?

A

Features

  • Autism
  • Development & speech delay
  • Behavior problems (ADHD)
  • Psychiatric disorders (anxiety, depression, bipolar)
  • Possibly birth defects
  • Under or overweight
  • Seizures possibly
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7
Q

What are the features of DiGeorge syndrome/22q11.2 microdeletion?

A

Features (CATCH22)

  • Cardiac defects
    • Tetralogy of fallot, interuped aortic arch type B, truncus arteriosus, VSD
  • Abnormal facies
    • Prominent tubular nose
    • Long fingers
    • High arched palate
    • upslanting palpebral fissures
  • Thymic hypoplasia
    • T-cell dysfunction, infections
  • Cleft palate
  • Hypocalcemia
  • Variable intellectual disability
  • Psychiatric disorders
  • hearing loss
  • Renal abnormalities
  • Endocrine abnormalities
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8
Q

What do ABCA3 mutations cause and what are the features?

A

Interstitial lung disease

Cause abnormality in surfactant

present in neonatal period with respiratory distress

Autosomal recessive

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9
Q

How is age-related macular dystrophy inherited?

A

Multifactorial

Age and family hx make up about 20% of risk

smoking and nutrition have an impact

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10
Q

What is the risk of developing age-related macular dystrophy if you have an affected FDR?

A

2-4 fold increased risk

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11
Q

What gene is associated with Alagille syndrome and what is the inheritance?

A

JAG1

autosomal dominant with variable penetrance

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12
Q

What are the features of Alagille syndrome?

A

Liver

  • Bile duct paucity causes green jaundice from direct bilirubin
  • leads to pruritus (itchy)
  • may have cirrhosis, liver failure
    • 10% die from this

Heart

  • Peripheral pulmonic stenosis
  • 25% die from congenital cardiac disease

Kidneys

  • Horseshoe kidneys

Eyes

  • Posterior embryotoxin

Bones

  • Butterfly vertebrae
  • Abnormal ribs

Abnormal lining of blood vessel

  • Strokes
  • Cerebral bleeds

Xanthomas (buildup of cholesterol over knees, elbows)

  • Because cholesterol doesn’t get released from the liver

Poor growth with short stature and low weight

Face

  • Triangular face, pointy chin, elfin looking
  • low set ears
  • broad forehead
  • deep eye, hypertelorism
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13
Q

What gene, types of mutations, and inheritance is associated with Albright’s Hereditary Osteodystrophy?

A

GNAS gene

loss of function mutations

autosomal dominant with imprinting (hormone resistance if inherited from mother)

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14
Q

What are the features of Albright’s Hereditary Osetodystrophy?

A

Features

  • Short
  • Obese
  • Round face
  • Developmental delay
  • Recessed 4th and 5th knuckles and toes
  • Resistance to PTH, TSH, growth hormone-releasing hormone, gonadotropin if inherited from mom
    • Resistance of gonadotropin leads to hypogonadism
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15
Q

What gene and genotype is associated with Alpha-1-Antitrypsin Deficiency?

A

SERPINA1 gene

ZZ genotype = affected

M & S allele normal and dominant

MZ carriers generally healthy, but can act as a modifier for other liver diseases

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16
Q

What are the features of Alpha-1-Antitrypsin Deficiency?

A

Liver disease in children

  • may or may not be present
  • if get to be age 4 or 5 without problems, they are probably fine
  • Hepatomegaly because of accumulation of abnormal AAT protein in the liver

Pulmonary disease in adults

  • Emphysema, COPD
  • Because the AAT protein is trapped in the liver and can’t break down and inactivate carcinogens

Increased risk for hepatocellular carcinoma

Avoid tobacco!

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17
Q

What are the genes associated with Alpha Thalassemia?

A

HBA1 and HBA2

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18
Q

What are the features of Alpha Thalassemia Trait/Minor/Alpha0?

A

Two gene deletion

Microcytic anemia

May be confused with iron deficiency

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19
Q

What are the features associated with HbH Alpha Thalassemia major?

A

3 gene deletion

Features

  • Splenomegaly
  • bone deformity
  • hemolytic and microcytic anemia
  • fatigue
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20
Q

What are the features of HbH + HbCS Alpha Thalassemia Major?

A

2 gene deletion + constant spring variant

Feaures

  • Splenomegaly
  • bone deformity
  • hemolytic and microcytic anemia
  • fatigue
  • More severe than HbH
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21
Q

What are the features what all 4 Alpha Thalassemia genes are deleted/mutated?

A

Hydrop Fetalis

All HbBarts

Not compatible with life

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22
Q

What do you see when testing for Alpha Thalassemia?

A

MCV <80fL

Will see HbBarts on newborn screen

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23
Q

What is the inheritance of Alport syndrome?

A

Most x-linked recessive

Some autosomal recessive

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24
Q

What are the features associated with Alport syndrome?

A

Progressive, later-onset sensorineural hearing loss

Kidney problems as presenting feature

  • (progressive glomerulonephritis)

Variable eye findings

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25
Q

What gene causes Anderson-Tawill syndrome and what is the inheritance?

A

KCNJ2

Autosomal dominant with variability

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26
Q

What are the features of Anderson-Tawill syndrome?

A

Significant cardiac manifestations

  • may need a pace maker
  • Can have sudden cardiac death

Myotonia (delayed muscle relaxation

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27
Q

What kind of disorder is Anderson-Tawill syndrome and what kind of test results do you see?

A

Channelopathy

Abnormal long exercise test

normal short exercise test

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28
Q

How is Angelman syndrome inherited?

A

Loss of functioning maternal UBE3A gene

  • deletion most common
  • paternal UPD 15
  • imprinting center defect (ICD)
  • UBE3A mutation (will have normal methylation)

Could be inherited from normal mother if mom inherited a deletion, ICD, or mutation from her father

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29
Q

How do you test for Angelman syndrome?

A

Methylation study

  • If abnormal, can do deletion analysis and/or UPD study to find out mechanism
  • If normal but still suspicion, sequence & del/dup UBE3A
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30
Q

What are the features of Angelman syndrome?

A

Features

  • Severe developmental and speech delay
    • Receptive communication > expressive
  • Hypotonia and feeding difficulties in infancy, tongue thrust or suck/swallowing disorders
  • Gait ataxia, wide based gait with hands raised while walking
  • Happy demeanor, happy puppet hands
  • Fascination with water
  • Seizures
  • Abnormal sleep cycles
  • Absolute or relative microcephaly by age 2
  • Prominent chin, wide mouth and wide spaced teeth, hyperpigmented skin, light hair/eyes, scoliosis, constipation
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31
Q

What gene is associated with Ataxia Telangiectasia and how is it inherited?

A

ATM

Autosomal recessive

Carriers at increased risk for breast cancer

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32
Q

What are the features of Ataxia Telangiectasia?

A

Features

  • Progressive cerebellar ataxia b/w 1-4 years
  • Oculomotor apraxia (eyes don’t work in symmetry)
  • Frequent infections, immunodeficiency
  • Choreoathetosis (dancing type movements that can’t be controlled)
  • Telangiectasias of the conjunctivae (lots of vessels in the sclera)
  • Increased risk for malignancy
    • Leukemia & lymphoma (1/3)
  • Sensitive to ionizing radiation
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33
Q

What cancers are associated with BAP1 mutations?

A

Uveal melanoma

cutaneous melanoma

renal cell carcinoma

mesothelioma

lung adenocarcinoma

meningioma

peritoneal serous adenocarcinoma

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34
Q

What genes are uveal melanoma associated with?

A

BAP1

BRCA2

CDKN2A

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35
Q

What gene and type of mutations are associated with Becker Muscular Dystrophy?

A

Dystrophin gene

Majority large deletions

In-frame deletions usually

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36
Q

How is Becker Muscular Dystrophy inherited?

A

X-linked recessive

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37
Q

What are the features of Becker Muscular Dystrophy?

A

Loss of ambulation >12 years

Looks like Duchenne Muscular dystrophy, but they do better

Isolated cardiomyopathy

Myalgias (muscle aches)

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38
Q

How is Beckwith-Wiedemann syndrome inherited?

A

Imprinting on chromosome 11

  • Same region as Russel-Silver syndrome

Mom’s copy is missing/mutated or dad’s copy is overexpressed

  • 50% hypomethylation of imprinting center 2 (IC2) on maternal copy
  • 20% paternal UPD
  • can be from gain of methylation of maternal CDKN1C, a microdeletion/duplication, or a translocation/inversion
  • Rarely autosomal dominant
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39
Q

What are the features of Beckwith-Wiedemann syndrome?

A

Features

  • Big baby
  • Omphalocele
  • Prematurity
  • Macroglossia
  • Asymmetry
  • Hypoglycemia
  • Umbilical hernia
  • Neonatal hypoglycemia
  • Ear creases/pits
  • Renal abnormalities
  • Overgrowth

Tumor risk

  • Wilms tumor
  • Hepatoblastoma
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40
Q

What tumor risks are associated with Beckwith-Wiedemann syndrome?

A

Wilms tumors

Hepatoblastoma

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41
Q

What gene is associated with Beta-Thalassemia?

A

HBB

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42
Q

What are the features of Beta-Thalassemia minor/intermedia?

A

B+/B+ or B+/B0

Mild anemia

later presentation

at risk for iron overload

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43
Q

What is thhe hemoglobin profile for someone with Beta-Thalassemia trait?

A

B/B+ or B/B0

A

Elevated A2

Fetal may or may not be elevated

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44
Q

What is the hemoglobin progile for someone with Beta-Thalassemia intermedia/minor?

A

B+/B+ or B+/B0

Elevated A2

Elevated Fetal

A present

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45
Q

What is the hemoglobin profile for someone with Beta-Thalassemia major?

A

B0/B0

Elevated A2

Elevated fetal

NO A

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46
Q

What are the features of Beta-Thalassemia major?

A

B0/B0

Features

  • Severe microcytic anemia
  • FTT, feeding difficulties, diarrhea
  • Frontal bossing, limb shortening, compression fractures of the spine
  • Hepatosplenomegaly
  • Jaundice
  • Iron overload
  • Extramedullary hematopoiesis
  • Endorine and liver issues
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47
Q

How is biotinidase deficiency inherited?

A

Autosomal recessive

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48
Q

What are the features of treated biotinidase deficiency?

A

No features if treated with biotin supplement

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49
Q

What are the features of untreated biotinidase deficiency?

A

If untreated

  • Sensorineural hearing loss
  • Seizures
  • vision loss
  • hair loss
  • Hypertonic
  • Developmental delay/intellectual disability
  • Ataxia
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50
Q

What gene is associated with Bloom syndrome and how is it inherited?

A

BLM gene

autosomal recessive

AJ founder mutation

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51
Q

What kind of syndrome is Bloom syndrome?

A

Chromosome breakage syndrome

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52
Q

What is the AJ carrier frequency of Bloom syndrome?

A

1 in 100 AJ carrier frequency

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53
Q

What are the features of Bloom syndrome?

A

Features

  • Pre- and postnatal growth deficiency
  • Microcephaly, dolichocephaly
  • malar hypoplasia
  • loss of lower lashes
  • Little subcutaneous fat
  • Facial telangiectatic erythemia & sun sensitive skin
  • Areas of hyper- and hypopigmentation
  • Possible learning disability, but normal intelligence
  • Males infertile, early menopause for women
  • More infections due to GER
  • Increased risk for DM, cancer, and COPD
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54
Q

How is brahio-oto-renal syndrome inherited?

A

Autosomal dominant

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55
Q

What are the features of brachio-oto-renal syndrome?

A

Hearing loss

  • conductive, sensorineural, or mixed

External ear abnormalities (pits or severely deformed)

Branchial cleft cysts or fistulae (lump in the neck or collarbone)

Kidney abnormalities

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56
Q

What gene is associated with campomelic dysplasia and what is the inheritance?

A

SOX9 cartilage gene

Autosomal dominant

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57
Q

What are the features of campoelic dysplasia?

A

Features

  • bent long bones (campomelia)
  • short stature
  • hearing loss
  • scolosis
  • Pierre-Robin sequence
  • sex reversal in males
  • club feet
  • problems with cartilage in the trachea
    • leads to severe air trapping
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58
Q

How is celiac disease inherited?

A

Multifactorial

Increased risk wit HLA-DQA1 adn HLA-DQB1 alleles

(3% with one or both of these alleles develops celiac, but 30% of the general population have one of the alleles)

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59
Q

What are the risks of developing Celiac disease if you have an affectd FDR?

A

5-10% risk if you have an affected FDR

40% risk if you have the same HLA profile as the affected FDR

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60
Q

What are the features of Celiac disease?

A

Autoimmune disorder to ingestion of gluten

  • Leads to inflammation of the small intestine and damage of villi, which can impair nutrient absorption

Signs/symptoms

  • Diarrhea, bowel irritability
  • Abdominal pain and distention
  • Weight loss
  • Vitamin deficiency, FTT, short stature, dental/enamel defects
  • Chronic fatigue
  • Joint pain/inflammation, osteoporosis/osteopenia
  • Depression, ADD
  • Infertility, fetal loss
  • Delayed puberty
  • Migraines
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61
Q

What gene is associated with CHARGE syndrome and what is the inheritance?

A

CDH7 gene

Autosomal dominant

majority de novo

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62
Q

What are the features of CHARGE syndrome?

A

Coloboma

  • Looks like a break in the iris and pupil is coming out

Congenital heart defect

  • ASD, VSD, mitral valve defects

Choanal atresia

  • Respiratory and feeding problems

Retardation of Growth and mental development

  • May mimic autism
  • Facial asymmetry, unilateral facial palsy from cranial nerve dysfunction

Genital defects

  • Genital hypoplasia, delayed puberty from hypogonadotropic hypogonadism

Ear malformations

  • May be deaf
  • External and internal malformations
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63
Q

What gene is associated with choroideremia and how is it inherited?

A

CHM gene

X-linked

Females have milder signs

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64
Q

What is choroideremia?

A

Progressive choroido-retinal degeneration

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65
Q

How does choroideremia present?

A

Males present with

  • early night blindness (not muc peripheral vision loss)
  • Central vision is preserved until later in life

Gene therapy trials

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66
Q

What population has a founder mutation for choroideremia?

A

Finish

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67
Q

What gene is associated with CLOVES syndrome and how is it inherited?

A

PIK3CA heterozygous somatic mutations

test skin, saliva, or affected tissue

de novo

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68
Q

What kind of syndrome is CLOVES syndrome?

A

Lipomatous overgrowth syndrome

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69
Q

What are the features of CLOVES syndrome?

A

Features

  • Congenital lipomatous asymmetric overgrowth
    • Of the trunk, lymphatic, capillary, and venous
    • Typically of the thoracic and abdominal wall
  • Combined-type vascular malformations
    • Low-flow and high-flow vascular and lymphatic malformations
  • Epidermal nevi
  • Skeletal and spinal anomalies
    • Can have various degrees of intellectual disability because of it
  • Renal anomalies
  • Tumors
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70
Q

How is CMT1 inherited?

A

Autosomal dominant

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71
Q

How is CMT2 inherited?

A

Autosomal dominant

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72
Q

What kind of neuropathy is CMT1?

A

Demyelinating

  • slow nerve conduction velocity
  • pathology of nerves has an onion appearance
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73
Q

What kind of neuropathy is CMT2?

A

Axonal

  • nerve conduction velocity near normal
  • decreased number of nerves
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74
Q

How is CMT4 inherited and what type of neuropathy is it?

A

Autosomal recessive

Axonal (decreased number of nerves)

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75
Q

How is CMTX inherited?

A

X-linked dominant

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76
Q

What is the most common form of CMT?

A

CMT1A

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77
Q

What gene and type of mutations is associated with CMT1A?

A

PMP22

Duplications (have 3 copies of PMP22)

  • 4 copies of PMP22 is severe CMT1
  • (A deletion of PMP22 causes hereditary neuropathy with liability to pressure palsy)
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78
Q

What are the features of CMT1A?

A

Onset 1st-2nd decade

Slow progression to orthotics

Foot deformities

foot drop

distal muscle weakness

distal muscle atrophy

sensory loss

slow nerve conduction

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79
Q

What genes are associated with Cockayne syndrome and what is the inheritance?

A

ERCC6 and ERCC2

autosomal recessive

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80
Q

What kind of syndrome is Cockayne syndrome?

A

Premature aging syndrome

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81
Q

What are the features of Cockayne syndrome?

A

Features

  • Progressive neurological and cognitive dysfunction (demyelination)
  • Microcephaly with developmental delay, spasticity, ataxia
  • Low birth weight and postnatal growth failure (Cahectic dwarfism)
  • Muscle atrophy, weight loss
  • Skin photsensitivity
  • Dental decay
  • Pigmentary retinopathy, optic atrophy, cataracts
  • Sensorineural hearing loss
  • vision loss, cataracts
  • Skeletal abnormalaties (kyphosis, scoliosis)
  • Prematurely aged face with deep set eyes and pinched nose
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82
Q

What gene is associated with Congenital Central Hypoventilation syndrome and how is it inherited?

A

PHOX2B

Caused by a decrease in a triplett repeat

Autosomal dominant

mostly de novo and/or mosaic

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83
Q

What are the features of congenital central hypoventilation syndrome?

A

Features

  • Apnea
  • Stop breathing when go to sleep
    • Absent respiratory response to hypoxia and hypercapnia, no change in respiratory effort during CO2 inhalation, illness, or exercise
    • Profound in sleep, especially non-REM sleep
  • Cyanosis
  • Cardiorespiratory arrest
  • Ophthalmologic abnormalities due to cranial nerves
  • Some have hirschprung (specific mutation)
  • Neural crest tumors
  • Arrhythmias
  • Some have seizures & cognitive disability
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84
Q

What is CHRPE (congenital hypertrophy of retinal pigmented epithelium) associated with?

A

FAP

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85
Q

How is congenital stationary night blindness inherited?

A

X-linked

Autosomal dominant

Autosomal recessive

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86
Q

what are the features of Congenital Stationary Night Blindness?

A

Night blindness

Contrast sensitivity

Nystagmus

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87
Q

What gene is associated with Cornelia de Lange and how is it inherited?

A

NIPBL gene mostly

Autosomal dominant

99% de novo

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88
Q

What are the features of Cornelia de Lange syndrome?

A

Features

  • Growth retardation
  • Facial
    • Long eyelashes
    • Thick eyebrows/synophorus, arched eyebrows
    • Upturned nose
    • Small widely spaced teeth
  • Microcephaly
  • Cognitive delay
  • Autistic and self-destructive tendencies
  • Shortened limbs
  • Missing digits
  • Genital abnormalities
  • GI dysfunction
  • Hearing loss
  • myopia
  • Cardia septal defects (VSD)
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89
Q

What causes Cri-du-Chat syndrome and how is it inherited?

A

5p-

loss of CTNND2, SEMA5A, possibly TERT

90% de novo, 80% from deletion of paternal copy

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90
Q

What is the sex ratio for Cri-du-Chat syndrome?

A

4:3 females:males

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91
Q

What are the features of Cri-du-Chat syndrome?

A

Features

  • Cat cry
  • Heart defects (VSD, ASD, PDA, Tetralogy of fallot)
  • Significant intellectual disability
  • Self-injury
  • Abnormal sleep patterns
  • Microcephaly
  • Hypotonia, poor feeding, Cleft lip/palate
  • Thymic dysplasia
  • Intestinal malrotation, megacolon, inguinal hernia
  • Dislocated hips
  • Rare renal malformations
  • Cryptorchidism, hypospadias
  • Hyperextensible joints
  • Scoliosis
  • Face
    • Hypoplastic nasal bridge
    • Hypertelorism, down-slanting palpebral fissures, Deep set eyes, prominent supraorbital ridges
    • Myopia, cataracts
    • Low-set ears with tags and/or fistulas
    • Micrognathia, cleft lip/palate
  • Short fingers
  • 2,3 syndactyly of hands and/or feet
  • Club feet, flat feet
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92
Q

How is Crohn’s disease inherited?

A

Multifactorial

29 genes, SNPS, and HLA status important

Environment, lifestyle, diet important

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93
Q

What are the symptoms of Crohn’s Disease?

A

Signs and symptoms

  • Weight loss, loss of appetite
  • Fever
  • Fatigue, night sweats
  • Loss of normal menstrual cycle
  • Mouth ulcers
  • Abdominal pain, diarrhea, bowel obstruction, rectal bleeding

Crohn’s disease

  • Mostly affects the ileum and entire thickness of the bowel wall
  • Can affect GI system anywhere from mouth to anus, and can “skip” areas

Ulcerative colitis

  • Affects the innermost lining of the colon/large intestine with no skipping
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94
Q

What are the main features of cystic fibrosis?

A

Lung disease from increased mucus

  • Poor genotype/phenotype correlation
  • Infection

Pancreatic insufficiency

  • Severe, classic mutations lead to pancreatic insufficiency
  • Milder, nonclassic mutations lead to pancreatic sufficiency

Infertility in males (>97%)

  • May be only feature
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95
Q

What are some symptoms of cystic fibrosis?

A

Features/signs

  • Affects the whole body
  • Night blindness
    • Can’t digest fat, so vitamins don’t get absorbed
  • Sterility in males due to CBAVD & decreased fertility in females
  • Digital clubbing
  • Osteoporosis
  • Diabetes
  • Cirrhosis
  • Dry, salty skin
  • Chronic pain
  • Liver disease
  • Can be associated with diabetes
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96
Q

How do you test for cystic fibrosis?

A

First line testing is sweath chloride test

Then do a panel of common mutations

  • can reduce carrier risk to 1 in 240

Can also do sequencing and del/dup

  • Can reduce carrier risk to 1 in 2500
  • Is this worth it for the family?
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97
Q

What gene is associated with cystic fibrosis and how is it inherited?

A

CFTR

autosomal recessive

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98
Q

What type of mutations are Class I CFTR mutations and how do you treat it?

A

Reduced or absetn transcription and protein

Read through therapy

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99
Q

What kind of mutations are Class II CFTR mutations and how do you treat it?

A

Protein is made, but it isn’t processed correctly and gets destroyed immediately. Never makes it to the cell surface

Gets destroyed becuase of protein misfolding, incomplete/incorrect post-translational modifications, or error in protein trafficking

Therapy would be correctors to help the protein fold properly and get to the cell surface

DeltaF508

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100
Q

What type of mutations are Class III CFTR mutations and how do you treat it?

A

Protein is made and it gets to the cell surface, but it doesn’t function properly

Treat with Kalydeco

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101
Q

What type of mutations are Class IV CFTR mutations?

A

Protein is made and gets to the cell surface, but it doesn’t work as well as it should. It is a little functional, though

R117H

  • If cis poly-T tract is 5T, it is disease causing because affects folding & gives alternate splicing
  • Having a higher TG tract with 5T makes it more likely to be disease causing because it leads to skipping of exon 9
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102
Q

What kind of mutations are Class V CFTR mutations?

A

There is reduced synthesis/protein production because of alternative splicing

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103
Q

What type of mutations are Class VI CFTR mutations?

A

Protein gets to the cell surface, but it is unstable and quickly get degraded

Rescued DeltaF508

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104
Q

What class of mutation is the CFTR DeltaF508?

A

Class II

Protein is made, but isn’t processed quickly and quickly gets destroyed

Once it has been treated with a corrector (helps fold the protein), it becomes a Class VI mutations (protein gets to the cell surface, but then gets quickly degraded)

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105
Q

What class of mutation if CFTR G551D and how do you treat it?

A

Class III (protein is made and gets to the cell surface, but it doesn’t function properly)

Treat with Kalydeco

Accounts for 4% of CF mutations

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106
Q

Explain pathogenicity of the poly-T tract and TG-tract in CFTR

A

Poly T tract:

  • The lower the poly T tract (5T), the more likely it is to be pathogenic
  • 5T, and potentially 7T can be pathogenic when in cis with R117H
  • Homozygous 5T can be at risk for male infertility
  • Lower T-tract is pathogenic because it can cause skipping of exon 9

TG-tract

  • Only pathogenic when in combination with 5T poly-T tract
  • The higher the TG-tract is (12 or 13), the more likely it is to be pathogenic when combined with 5T
  • 5T with 12 or 13 TG tract without R117H mutation can cause nonclassic disease
  • A higher TG tract can lead to skipping of exon 9
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107
Q

What gene is associated with Connexin 26 and how is it inherited?

A

GJB2

Autosomal recessive

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108
Q

What features is Connexin 26 associated with?

A

Non-syndromic congenital sensorineural hearing loss

(DFNB1)

Milder presentation for compound heterozygotes

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109
Q

What percentage of hearing loss is due to Connexin 26?

A

10-15% of all hearing loss

50% of autosomal recessive hearing loss

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110
Q

What is the carrier frequency for Connexin 26?

A

1 in 31-35 for Caucasians

1 in 21-25 for AJ

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111
Q

How is diabetes inherited?

A

Multifactorial

  • Genetics (stronger for Type II)
  • diet, exercise, weight (74% of risk for Type II)
  • HLA status
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112
Q

What type of diabetes has a stronger genetic component?

A

Type II

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113
Q

What is the chance of developing diabetes if you have one parent with Type II diabetes?

A

1 in 10

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114
Q

What is the chance of developing diabetes if you both parents have Type II?

A

1 in 2

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115
Q

How is MODY inherited?

A

Autosomal dominant

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116
Q

What percentage of diabetes is MODY?

A

1-2% of diabetes is MODY

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117
Q

Why is it important to identify MODY?

A

MODY has an effective treatment (sulfonylureas), which does not work for other types of diabetes

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118
Q

How is DICER1 inherited?

A

Autosomal dominant

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119
Q

What cancers are associated with DICER1 mutations?

A

Pleuropulmonary blastoma (PPB)

Cystic nephroma

Ovarian Sertoli-Leydig tumor

Other sex-cord stromal tumors

Wilms tumor (rare)

Intraocular medulloepithelioma

Nasal chondromesenchymal hamaroma (present with stuffy nose)

Thyroid (nodular thyroid hyperplasia, differentiated thyroid carcinoma)

Embryonal rhabdomyosarcoma

Intestinal hamartomatous polyps

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120
Q

When is the cancer risk greatest for DICER1 mutations?

A

The cancer risk is greatest when young

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121
Q

How does pleuropulmonary blastoma (PPB) present and what should you test for when you see it?

A

PPB may present as a spontaneous pneumothorax

Test for DICER1

60-70% of these cases are from DICER1 mutations

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122
Q

What should you test for when you see a cystic nephroma?

A

DICER1

90-100% are due to DICER1 mutations

2/3 of cystic nephroma cases without a family history of PPB have a DICER1 mutation

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123
Q

What should you test for when you see an ovarian sertoli-leydig tumor?

A

DICER1

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124
Q

What gene, types of mutations, and inheritance is associated with Duchenne Muscular dystrophy?

A

Dystrophin gene

Out of frame deletions

X-linked recessive

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125
Q

What are the features of Duchenne Muscular Dystrophy?

A

Features/presentation

  • Inability to run/keep up around age 3
  • Gower maneuver
  • Difficulty climbing stairs
  • Gait abnormalities/toe walking
  • Calf hypertrophy (pseudohypertrophy from fatty infiltration)
  • Proximal leg weakness, progressing to arms
    • Wheelchair confined by age 12
    • Can’t life arms very high
  • Scoliosis because muscles can’t hold them up
    • Squishes lungs and leads to respiratory issues
  • Sleep disorders due to extra shallow breathing
  • Can’t take deep breaths or cough properly
  • Dilated cardiomyopathy
  • Mild obesity (because of steroids)
  • Mild mental retardation
  • CK levels 50-100x normal
  • Death due to pneumonia or congestive heart failure (DCM) in 20s
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126
Q

What are the features of a female carrier of Duchenne Muscular dystrophy?

A

Muscle aches

May have elevated CK levels

May be more severely effective due to mosaicism (10%) or skewed X-inactiation

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127
Q

If a boy is a simplex case of Duchenne muscualr dystrophy, what are the chances his mom is a carrier?

A

2/3 (1/3 of cases are de novo)

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128
Q

What are some potential therapies being researched for Duchenne muscular dystrophy?

A

Stop codon readthrough
Exon skipping therapies

  • Make an out of frame deletion and in-frame to give BMD phenotype
  • Restores reading frame in ~13%
  • Gives some expression of dystrophin

Gene transfer therapy

  • Myostatin inhibitor to get hypertrophy
    • Decreases severity of disease

Gene replacement

  • Mini-dystrophin in vector

Surrogate gene transfer of Galgt2

  • Restores CK levels
  • Doesn’t induce immunity because the gene is already expressed
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129
Q

What are the features of Classic EDS (Type 1) and how is it inherited?

A

COL5A1 gene, autosomal dominant

Features

  • Skin hyperextensibility
  • fish mouth or cigarette paper scars
  • joint hypermobility
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130
Q

What are the featues of EDS Type 3 (Hypermobile type)?

A

Major criteria

  • Smooth, velvety skin
  • Joint hypermobility

Minor criteria

  • Chronic joint/limb pain
  • Recurrent joint dislocations
  • Positive family hx

Other features

  • Narrow, high arched palate
  • Scoliosis
  • Flat feet
  • Valgus deformity
  • Marfanoid habitus, but don’t meet Marfan criteria
  • Pectus excavatum (carinatum more rare)
  • Constipation, IBS, GER
  • Family hx of fibromyalgia
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131
Q

How is EDS Type 3 (Hypermobile type) inherited and diagnosed?

A

Autosomal dominant

Clinical dx only, no known gene

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132
Q

What gene is associated with EDS Type 4 (vascular type) and how it is inherited?

A

COL3A1

Autosomal dominant

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133
Q

What are the features of EDS Type 4 (vascular type)?

A

Features

  • Arterial, bowel, and uterine ruptures
  • Pneumothorax
  • Postpartum bleeding
  • Lobeless ears
  • Acrogeria (premature aging, hands may look really old)
  • Translucent skin (seen veins)
  • A little bit of joint hypermobility
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134
Q

What type of disorder is Farbry disease?

A

Lysosomal storage disorder

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135
Q

What gene is associated with Fabry disease and how is it inherited?

A

GLA gene

X-linked recessive with varied symptoms in females

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136
Q

What are the features of Fabry disease?

A

Features

  • Pain in distal extremities
  • Heat intolerance
  • Angiokeratomas on trunk
  • GI dysfunction
  • Renal disease
  • Cardiomyopathy
  • Stroke
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137
Q

How can you treat Fabry disease and how does it help?

A

ERT available, but not 100% effective

  • Decreases vascular lesions
  • Increases renal and myocardial function
  • Decreases pain
  • Increases heat/cold tolerance by improving nerve conduction
  • Improve exercise intolerance
  • Improves quality of life
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138
Q

What are the genetics behind facio-scapulo-humeral muscular dystrophy?

A

4q35 regions
Need to do southern blot to detect
D4Z4 repeat encodes DUX4

  • Causes myopathy via a p53 dependent pathway

Get disease when have reduce repeats (1-10) and 4QA allele (makes poly-A tail)
Not a trinucleotide repeat where size varies between generations
1:20,000-435,000

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139
Q

What are the features of facio-scapulo-humeral muscular dystrophy (FSHMD)?

A

Facial weakness

  • Tapered lip, can’t smile well, can’t squeeze eyes shut, chiseled cheek bones, can’t pucker lips, many can’t drink through a straw

Scapula stick out
Peroneal and hip girdle weakness later
Weakness in pectoral muscles and biceps

  • Atrophic biceps with maintained deltoids

Can’t lift arms very high
Hypertrophy of forearms
Sensorineural deafness
Retinal vascular tortuosity possible
Absent brachio-radialis
Bulbar, extraocular, and respiratory muscles spared

asymetric onset and progression

Relatively normal CK

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140
Q

What is the Factor V Leiden mutation?

A

F5 gene

p.Arg506Gln, 1691G>A

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141
Q

What are the risks associated with Factor V Leiden?

A

Venous thromboembolism (VTE) (deep vein thrombosis)

  • Heterozygous: 3-8x increased risk for VTE (<10%)
  • Homozygous 50-80x increased risk for VTE (<10%)
  • Risk increases with age
  • No impact on risk for a recurrent VTE

Pulmonary emboism

Small increased risk (2-7 fold increased risk) for pregnancy loss and pregnancy complications

Other risk factors include pregnancy, oral contraceptives/HRT, cancer, age, obesity, surgery, injury

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142
Q

What gene is associated with FAP and how is it inherited?

A

APC (many mutations not detected)

Autosomal dominant

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143
Q

When should you test for FAP?

A

Age 10-12

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144
Q

What risks are associated with FAP?

A

Colon cancer

  • 100s-1000s of polyps
  • risk 100% if untreated

Extracolonic tumors

  • Upper GI
  • Desmoid
  • Osteoma
  • Thryoid
  • Brain
  • Soft tissues tumors
  • hepatoblastoma
    • 2% risk
  • CHRPE
  • Dental anomalies
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145
Q

What gene is associated wtih Familial Mediterranean Fever and how is it inherited?

A

MEFV gene (sequence only)

Autosomal recessive

High carrier frequency in Turkey & North African Jewish (1:5), and Armenian (1:7)

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146
Q

What are the features of Familial Mediterranean Fever?

A

Features

  • Recurrent fevers in childhood may be only manifestation
  • Abdominal attacks (90%)
    • Recurrent, acute fevers with intense abdominal pain
  • Articular attacks (75%)
    • High fever and joint pain, can lead to chronic joint pain
  • Pleural attacks (45%)
    • High fever with chest pain & painful breathing
  • Erysipelas-like erythema
    • Lesion on lower limb often accompanied by a fever or arthritis
  • Amyloidosis (Build up of AA amyloids in kidneys)
    • can lead to end stage renal disease (presents with proteinuria)
147
Q

How is Fanconi Anemia inherited and what are some genes associated with it?

A

Mostly autosomal recessive

FANCB is X-linked

Homozygous BRCA2 and PALB2 cause Fanconi anemia

FANCC gene has a common AJ mutation

15 genes

148
Q

What type of syndrome is Fanconi Anemia?

A

Chromosome breakage syndrome

149
Q

What are the features of Fanconi Anemia?

A

Features

  • Progressive bone marrow failure (usually in 1st decade, 90% by 4th-5th decade)
  • Short stature
  • Abnormal skin pigmentation, Café-au-lait spots
  • Skeletal, thumb, forearm malformation, radial ray anomalies
  • Ocular issues
  • Kidney/urinary disease, GI abnormalities
  • Hearing loss
  • Heart defects (VSD)
  • Developmental delay
  • Underdeveloped pituitary, hypogonadism
  • Cancer
    • Hemotolagic (10-30%)
    • Head and neck, GI, genital tract (25-30%)
150
Q

What gene is associated with fibroadipose hyperplasia and how is it inherited?

A

PIK3CA heterozygous somatic mutations

(test skin, saliva, or affected tissue)

De novo

151
Q

What kind of syndrome is fibroadipose hyperplasia?

A

Lipomatous overgrowth syndrome

152
Q

What are the features of fibroadipose hyperplasia?

A

Features

  • Cutaneous capillary vascular malformations
  • Testicular or epidymal abnormalities
  • Epidermal nevi
  • Polydactyly
153
Q

How common is autism in Fragile X syndrome?

A

25% have an autism spectrum disorder

154
Q

What are the features of Frasier Syndrome?

A

Genetically male (XY)

ambiguous genitalia

kidney problems (focal segmental glomerulosclerosis)

gonadoblastoma

Wilms tumor

155
Q

What gene is associated with Galactosemia and how is it inherited?

A

GALT gene

autosomal recessive

156
Q

What kind of disorder is galactosemia and how is it treated?

A

Disorder of carbohydrate metabolism

Treat by eliminating galactose from the diet

157
Q

What are the features of galactosemia?

A

Features

  • Failure to thrive
  • Hepatomegaly
  • Cataracts
  • Speech and developmental problems when not treated
  • Vomiting, diarrhea, dehydration
158
Q

What gene is associated with Gaucher and how is it inherited?

A

GBA gene

autosomal recessive

159
Q

What kind of disorder is Gaucher disease?

A

Lysosomal storage disorder

160
Q

What are the features of Gaucher disease?

A

Features

  • Hepatosplenomegaly
  • Cytopenia
  • Gaucher cells (pathoneumonic)
  • Erlenmeyer flask shape to bones
  • Vascular necrosis
161
Q

How do you treat Gaucher Disease and how does it help?

A

Enzyme replacement therapy available

  • Decreases hepatosplenomegaly
  • Improves liver and spleen function
  • Improves bone manifestations
  • Helps with growth
162
Q

Do you test for glaucoma?

A

No

163
Q

What gene is associated with hemochromatosis and how is it inherited?

A

HFE gene

(C282Y adn H63D)

Autosomal recessive

164
Q

What are the features of hemochromatosis?

A

Increased iron accumulation

  • can lead to diabetes
  • hyperpigmentation of skin (bronze)
  • arthritis
  • CV issues

Treat with phlebotomy

165
Q

What genes (protein deficieny) are associated with hemophilia, how is it inherited, and which typie is more common?

A

F8 gene, Factor VIII deficiency, Hemophilia A, most common

F9 gene, Factor IX deficiency, Hemophilia B

X-linked

166
Q

What are the symptoms of a hemophilia carrier, and what is the chance of being a carrier?

A

Symptoms

  • Mild hemophilia
  • menorrhagia
  • bleeding with tooth extraction, trauma, etc
  • easy bruising

Obligate carrier is father is affected, 2 sons affected or 1 affected sone and 1 affected maternal relative

If son is a simplex case

  • 30% chance the son is a de novo case
  • Mom could have a de novo mutation
    • common with inversion 22, which occurs during spermatogenesis 90% of the time
  • Mom could have inherited it from her mom
167
Q

What are the features of hemophilia?

A

Hemorrhage (spontaneous or with incidental injury)

Joint or deep muscle bleeds (severe)

bleeding after mild trauma, minor procedures, surgery

Severe <1% factor

Modertae 1-5% factor

Mild 6-35% factor

168
Q

When/why would you do genetic testing for hemophilia?

A

Carrier screening, prenatal testing, or confirming a diagnosis

To figure out inhibitor risk

  • Genotype/phenotype correlation with this
  • inversion22 has a high risk for inhibitors
169
Q

What gene & mutation is associated with Hereditary Neuropathy with Liability to Pressure Palsy (HNPP)?

A

Deletion of PMP22 (only have 1 copy of PMP22)

Can also be PMP22 point mutations

(Duplication of PMP22 causes CMT1A)

170
Q

What are the features of Hereditary Neuropathy with Liability to Pressure Palsies?

A
  • Young adult onset
  • mild axonal peripheral neuropathy
  • tomauli are a pathological hallmark (looks like sausages)
171
Q

What genes are associated with hereditary pancreatitis?

A

CFTR

PRSS1

SPINK-1

172
Q

What are some features of Hermansky-Pudlak?

A

May appear like albinism

normal or decreased vision

Many die from bleeding diathesis

2 founder mutations in Puerto Rico

173
Q

What gene is associated with Hunter syndrome and how is it inherited?

A

IDS gene

x-linked

174
Q

What type of disorder is Hunter syndrome?

A

Mucopolysaccharidosis

175
Q

What are the features of Hunter syndrome?

A

Features

  • Coarse facial features (gets worse over time)
  • Hepatosplenomegaly
  • Joint contractures
  • Developmental delay/intellectual disorders
  • Limited range of motion
176
Q

How is Hunter syndrome treated and what does it help?

A

ERT available

  • Decreases GAGS
  • Improves hepatosplenomegaly
  • Improves airway problems (often have storage in their airway)
  • Improves sleep apnea
  • Improves motor function
  • Improves myocardial function
  • Improves range of motion in joints
  • Give better growth rate
177
Q

What gene & types of mutations are associated with Huntington Disease, and how is it inherited?

A

HTT gene

Autosomal dominant with anticipation

CAG trinucleotide repeat

  • 10-27 repeats normal
  • 28-35 repeats normal, but risk for expansion
  • 36-39 reduced penetrance, risk for expansion
  • 40+ repeats=disease
178
Q

What are the features of Huntington Disease?

A

Features

  • Progressive neurodegeneration
  • Unseteady gait and involuntary movements
  • Personality changes, mood swings, outbursts, depression, OCD
  • Forgetfulness, impaired judgement, decreased memory, reasoning, and concentration
  • Slurred speech and difficulty swallowing
  • Onset 30s-40s, live 15-20 years after onset
179
Q

What gene is associated with Hurler syndrome and how is it inherited?

A

IDUA

autosomal recessive

180
Q

What kind of disorder is Hurler syndrome?

A

Mucopolysaccharidosis

181
Q

What are the features of Hurler syndrome?

A

Features

  • Coarse facial features
  • Hepatosplenomegaly
  • Corneal clouding
  • Joint contractures & limitations
  • Developmental delay/intellectual disorders
  • Macroglossia
  • Dysostosis multiplex (bone involvement)
  • Deafness
  • Valvular heart disease
182
Q

How is Hurler syndrome treated and what does it help with?

A

Bone marrow transplant

ERT available

  • Decreases GAGS
  • Improves hepatosplenomegaly
  • Improves airway problems (often have storage in their airway)
  • Improves sleep apnea
  • Improves motor function
  • Improves myocardial function
  • Improves range of motion in joints
  • Give better growth rate
183
Q

What is the difference between Hunter syndrome and Hurler syndrome?

A

Hunter syndrome is X-linked

Hurler syndrome has corneal clouding

184
Q

What gene is associated with Hyperkalemic Periodic Paralysis and how is it inherited?

A

SCN4A gene

Autosomal dominant

185
Q

What are the features of Hyperkalemic Periodic Paralysis?

A
  • Periodic paralysis
    • triggers include exercise, fasting, or cold exposure
  • myotonia
  • Problems with anesthesia
  • Inconsistently high serum potassium levels
186
Q

What kind of disorder is Hyperkalemic Periodic Paralysis and what tests can be done to look for it?

A

Channelopathy

Abnormal long exercise test, normal short exercise test

187
Q

What genes are associated with Hypohidrotic Ectodermal Dysplasia and how is it inherited?

A

EDA, X-linked, most common

EDAR, autosomal recessive

EDARADD, autosomal dominant

IKKG, NEMO, X-linked (immune deficiency)

188
Q

What are the features of hypohidrotic ectodermal dysplasia?

A

Features

  • Thin, peely skin
  • Fine, dry hair, doesn’t grow well, abnormal pattern (HYPERTRICHOSIS)
  • Don’t sweat (HYPOHIDROSIS)
  • Hypoplastic or absent mucous glands
  • Hypodontia or anodontia with conical shaped teeth (HYPODONTIA)
  • May have low immune system with recurrent infections
189
Q

What gene is associated wtih hypokalemic periodic paralysis and how is it inherited?

A

CACNA1S and SCN4A

Autosomal dominant

190
Q

What kind of disorder is hypokalemic periodic paralysis and what test can you do to look for it?

A

Channelopathy

abnormal long exercise test, normal short exercise test

191
Q

What are the features of hypokalemic periodic paralysis?

A
  • Hours to days of muscle weakness
  • Can awak with paralysis
    • usually hours after exertion or a carbohydrate rich meal
  • Low potassium levels
  • can have problems with anesthesia
  • NO myotonia present
192
Q

What gene is associated wtih Incontinentia Pigmenti and how is it inherited?

A

IKBKG gene

X-linked dominant

lethal in males

193
Q

What are the features of Inconteinentia Pigmenti?

A

Skin lesions

  • Progress from herpes appearing lesions, to severe burn appearing lesions, to hyperpigmentation, to hypopigmented lesions

CNS Problems

  • developmental delay (including cognitive)
  • seizures
  • microcephaly
  • spasticity
  • paralysis

Dental manifestations

  • Late dentition, hypodontia, conical teeth

Ocular manifestations

  • Strabismus, neovascularization, microphthalmos, optic nerve atrophy, cataracts, glaucoma
194
Q

What causes Jacobsen syndrome?

A

11q terminal deletion

slightly more common in females

195
Q

What are the features of Jacobsen syndrome?

A

Features

  • Heart defects (VSD, hypoplastic left heart)
  • Kidney defects
  • FTT, feeding difficulties, pyloric stenosis
  • Recurrent infections (ear, respiratory)
  • Short stature, skeletal abnormalities
  • High bleeding risk (Paris-Trousseau)
    • ​20% die by age 2 from heart and bleeding problems
  • Developmental delay with mild to severe mental retardation
  • OCD, ADHD, short attention span
  • Facial
    • Macrocephaly, trigonalcephaly
    • Low set ears
    • Hypertelorism, ptosis, epicanthal folds, strabismus, coloboma
    • Broad nasal bridge, thin philtrum, micorgnathia, downturned mouth
196
Q

What genes are associated with Jervell and Lange-Nielson syndrome and how is it inherited?

A

KCNQ1 and KCNE1

Autosomal recessive

Homozygous form of long QT syndrome

197
Q

What are the features of Jervell and Lange-Nielson syndrome?

A

Risk of sudden death

Congenital sensorineural hearing loss

Fainting

Both parents have long QT syndrome

198
Q

What features are associated with Leber Congenital Amaurosis?

A

Congenial severe vision loss

nystagmus

Group of disease, lots of genes

199
Q

How is Leber Hereditary Optic Neuropathy inherited and who is affected?

A

Mitochondrial inheritance

heteroplasmy may affect phenotype

5:1 male:females affected

200
Q

What are the features of Leber Hereditary Optic Neuropathy?

A
  • Bilateral, painless, subacute visual failure
    • First color vision profoundly affected (especially red/green)
    • Then develops to blurred central vision, loss of central vision (peripheral vision spared)
  • Most have isolated optic neuropathy, some have systemic neuropathy
    • Tremors, myopathy, ovement disorders
  • Cardiac arrhythmias
  • Rapid optic nerve death
  • Onset late teens to early 30s, women develop later and may have an MS-like phenotype
201
Q

What gene is associated with Legius syndrome and how is it inherited?

A

SPRED1 gene

autosomal dominant

202
Q

What are the features of Legius syndrome?

A
  • Isolated cafe-au-lait spots
    • important to differentiate from NF1 because screening is not needed
  • freckling
  • macrocephaly
  • intellectual disability
203
Q

What cancers are associated with Li-Fraumeni syndrome?

A

Cancers

  • Early onset bone sarcoma (except Ewing)
  • Early onset soft tissue sarcoma
  • Osteosarcoma
  • Early onset breast cancer
  • Adrenocortical carcinoma (50-80% of these are TP53)
  • Choroid plexus carcinoma (36-100% of these are TP53)
  • Rhabdomyosarcoma <3 years (~25% of these are TP53)
  • Brain tumors
  • Multiple primary tumors, especially with radiation
  • 70% risk for males, 100% for females
204
Q

What should you test for if you see adrenocortical carcinoma?

A

TP53/Li-Fraumeni

50-80% of these are due to TP53 mutations

205
Q

What should you test for if you see choroid plexus carcinoma?

A

TP53/Li-Fraumeni

36-100% of these are due to TP53 mutations

206
Q

What gene should you think about when you see rhabdomyosarcoma?

A

TP53/Li-Fraumeni

~25% of these are due to a TP53 mutation

207
Q

What is the Classic criteri for Li-Fraumeni syndrome?

A
  • Proband <45 with sarcoma AND
  • FDR <45 with any cancer AND
  • 3rd family member who is FDR or SDR <45 with cancer, or sarcoma at any age
208
Q

What are the Li-Fraumeni testing criteria and how likely are you to find a TP53 mutation?

A
  • Proband with any childhood cancer, or sarcoma, brain tumor, or adrenocortical tumor <45 AND
  • FDR or SDR with LFS cancer at any age AND
  • another FDR or SDR with any cancer <60

20% chance of having a TP53 mutation if meet this criteria

209
Q

How are Limb-Girddle Muscular Dytrophy Type 1 (LGMD1) disorders inherited?

A

Autosomal Dominant

210
Q

How are Limg-Girddle Musculary Dystrophy Type 2 (LGMD2) disorders inherited?

A

Autosomal recessive

211
Q

What are the features of limb-girddle muscular dystrophies?

A
  • Affect the voluntary proximal muscles of the shoulder, hips, thighs, and top part of the arm
  • Waddling gait
  • Difficulty running, standing, climbing stairs. Fall frequently
  • Trouble raising and holding arms above head and carrying objects
  • Scapular winging, lordosis, scoliosis, contractures, calf hypertrophy
  • Cardiomyopathy or arrhythmia
  • Difficulty breathing
212
Q

What can you do to test for a limb-girddle muscular dystrophy?

A

CK levels are elevated

Muscle biopsy

EMG

Genetic testing with a panel

213
Q

What gene is associated with Marfan syndrome and how is it inherited?

A

FBN1 gene (gain-of function mutation leads to decreased myofibrils, nonsense mutations lead to haploinsufficiency)

Autosomal dominant

214
Q

What features are associated with Marfan syndrome?

A

Features

  • Tall stature
  • Decreased upper segment/lower segment ratio
  • Arm span exceeds height
  • Dolichocephaly (long back of head)
  • Long, slender, curved fingers
  • Pectus carinatum/excavatum
  • Malar hypoplasia (flat cheeks)
  • Retinal detachment
  • Lens sublaxation or dislocation (ectopia lentis)
  • High myopia
  • Megalocornia
  • Long, spider fingers
  • Scoliosis
  • Flat feet
  • Pneumothorax
  • Striae not associated with marked weight change
  • Family hx of sudden death
  • Heart defects
    • Aortic aneurysm, aortic root dilation–>sudden death
215
Q

What are the features of a baby born to a mom with uncontrolled PKU?

A

Microcephaly

mental retardation

congenital heart disease

light colored hair

216
Q

What gene is associated with McCune Albright syndrome and how is it inherited?

A

GNAS gene (activating mutation)

Always somatic mosaicism, never inherited (don’t do genetic testing)

217
Q

What are the features of McCune Albright syndrome?

A

Features

  • Polyostotic fibrous dysplasia (scar-like tissue in bones leading to uneven growth & fractures)
    • Age 3-10
    • Facial-painless lumps, asymmetry, loss of vision/hearing rare
    • Skeletal-limping, pain, fractures
    • scoliosis
  • Café-au-lait like spots
    • Irregular borders (coast of Maine), not smooth, defined borders
    • First sign
  • Early puberty in girls
  • Thyroid lesions/disease (hyperthyroid)
  • Hypophosphatemia (severe skeletal involvement, fractures, bone pain)
  • Excess growth hormone
  • Neonatal Cushings syndrome-rare
  • Can also have malignancies, polyps, and cardiac involvement
218
Q

What gene is associated with Megalencephaly-Capillary Malformation Syndrome (MCAP), and how is it inherited?

A

PIK3CA gene

Heterozygous somatic mutations

  • test skin, saliva, or affected tissue

De novo

219
Q

What kind of disorder is Megalencephaly-Capillary Malformation Syndrome (MCAP)?

A

Brain overgrowth syndrome

220
Q

What are the features of Megalencephaly-Capillary Malformation Syndrome (MCAP)?

A

Features

  • Congenital or early post-natal megalencephaly
    • Can have ventriculomegaly and hydrocephaly, cortical brain malformation and polymicrogyria
  • Segmental or generalized overgrowhth
  • Midline facial capillary malformation
  • Hypotonia
  • Intellectual disability
  • Autistic features
  • Epilepsy
  • Cutaneous syndactyly
  • Coarse facial features with frontal bossing
  • Heart defects (VSD, ASD)
  • GI problems
  • Tumors
221
Q

What gene is associated with Menkes disease and how is it inherited?

A

ATP7A gene

X-linked recessive

222
Q

What causes Menkes syndrome?

A

Copper deficiency

  • copper doesn’t get absorbed correctly from the intestine
  • Copper builds up in some tissues (small intestine & kidneys)
  • Low copper levels in brain and other tissues
223
Q

What are the features of Menkes syndrome?

A

Features

  • Hypotonia
  • Kinky, brittle hair
  • Fragile skin, skin laxity
  • Hypopigmented skin
  • Umbilical or inguinal hernia
  • Pectus excavatum
  • Temperatures instability
  • hypoglycemia
  • Occipital horn in skull
  • Seizures
  • Failure to thrive
  • Neurodevelopmental delay & neurologic issues
  • Gastric polyps
  • Wormian bone
  • osteoporosis
224
Q

How is Menkes syndrome treated and what is the prognosis?

A

Treat with copper injections

Usually die around 9 months

225
Q

What gene is associated with myotonia congenita and how is it inherited?

A

CLCN1 gene

Can be dominant (Thomsen myotonia congenita)

Can be recessive (Becker myotonia congenita)

226
Q

What are the features of Myotonia congenita?

A
  • Warm-up phenomenon
  • onset childhood to young adulthood
  • Myotonia (delayed muscle relaxation)
227
Q

What kind of disorder is myotonia congenita and how can you test to look for it?

A

Channelopathy

Abnormal short exercise test (repeated drops and rises because of warm-up phenomenon)

Normal long exercise test

228
Q

What gene is associated with myotonic dystrophy type 1 and how is it inherited?

A

DMPK gene

Autosomal dominant with anticipation

CTG Triplett repeat expansion

  • 35-49 repeats-asymptomatic premutation
  • 50-~150 repeats-mild presentation
  • ~100-~1000 repeats-classic presentation
  • >1000 repeats-congenital myotonic dystrophy

Expands through the mother

229
Q

What are the features of myotonic dystrophy?

A
  • Myotonia
  • gait disturbance, weakness
  • Cataracts with Christmas tree appearance
  • Frontal balding, Ptosis and myotonic mouth
  • Arrhythmia, cardiomyopathy (cause of death)
  • Anxiety/depression, Hypersomnia, sleep apnea
  • Minor cognitive delay
  • Thyroid dysfunction
  • Diabetes
  • Testicular atrophy, gynecomastia, infertility
  • Constipation
  • Difficulty swallowing, dysphagia
  • Onset typically 20s-30s,
  • Death typically 48-55 years
  • Due to respiratory difficulty and/or cardiac disease
230
Q

How is Nemaline Myopathy inherited?

A

Autosomal dominant and autosomal recessive

de novo

9 genes

one gene common in Amish communities

231
Q

What are the features of Nemaline myopathy?

A

Severe congenital, congenital, and childhood-onset forms

  • Severe congenital form is often lethal, severe hypotonia, GER, respiratory insufficiency
  • Amish form is lethal in early childhood, hypotonia, contractures, tremors, pectus carinatum, muscle atrtophy
  • Intermediate congenital form has contractures, weakness, need for wheelchair & ventilator support by 11
  • Typical congenital has hypotonia, feeding difficulties, delayed motor milestones, waddling gait, bulbar and proximal weakness, nocturnal hypoventilation, recurrent infections, slow/static progressive weakness
  • Childhood onset 1st-2nd decade onset, foot drop, muscle slowness, slowly progressive
  • Adult onset 20-50 years, myalgia, cardiomyopathy, head drop, rapid progression
  • CK levels normal to mildly elevated
  • Muscle biopsy shows nemaline rods with Gomori tricome stain
232
Q

What gene is associated with Neurofibromatosis 1 and how is it inherited?

A

NF1 gene

Autosomal dominant

50% de novo

233
Q

What is NF1 diagnostic criteria?

A

Diagnosis (2 of the the following) is highly specific (~50% meet by age 1 without family hx)

  • Skin lesions
    • Café-au-lait spots
      • ≥6 lesions over 5 mm when pre-pubertal, over 15mm if post-pubertal
        • Tend to grow and get bigger with the child
    • Plexiform neurofibromas
      • Tend to be invasive
      • Can be hard or soft
      • Earlier onset
    • ≥2 neurofibromas
      • Can be internal and never seen
      • Post-pubertal onset
    • Axilla and/or inguinal skin freckling
  • Eye findings
    • Lisch nodules
      • In 90% of patients over age of 6
      • Iris hamartomas, don’t affect vision
    • Optic nerve glioma
      • Develop before age 6
      • 3% become malignant, but can also spontaneously regress
      • May not affect vision, but can lead to blindness
  • Family history of NF1
  • Skeletal Features
    • Sphenoid wing dysplasia (bone pushes eye out)
      • Usually unilateral
    • Pseudo-arthrosis bowing
      • Almost like a second joint that causes bowing in the leg or arm
      • These bones tend to be fragile and fracture
234
Q

What NF1 features are present in infancy or preschool?

A

Plexiform neurofibroma

tibial dysplasia

cafe-au-lait

developmental delay (mainly speech)

235
Q

What NF1 features are present in school age children?

A

Optic glioma (by age 6)

lisch nodules

short stature

hypertension

cafe-au-lait

236
Q

What NF1 features are present in adolescence?

A

Dermal neurofibroma

scoliosis

hypertensin

cafe-au-lait

237
Q

What NF1 features are present in adulthood?

A

Neurofibromas

Cafe-au-lait

Breast, thyroid, colon cancer (low risk)

Hypertension

238
Q

What gene is associated with neurofibromatosis 2 and how is it inherited?

A

NF2 gene

Autosomal dominant

  • 1/3 somatic mosaicism
239
Q

What are the features of NF2?

A

Hearing loss

  • from bilateral vestibular schwannoma
  • can be presenting feature

High risk for tumors

  • bilateral vestibular schwannoma
  • schwannomas of other cranial and peripheral nerves (60%)
  • meningiomas (50%)
  • Ependymomas (rare)
  • Astrocytomas (rare)

Facial nerve palsy or other single nerve disorder compromise

240
Q

What kind of disorder is Noonan syndrome?

A

Rasopathy

241
Q

What features are associated with Noonan syndrome?

A

Cafe-au-lait spots

congenital heart defects (PVS, PDA, hypertrophic cardiomyopathy)

Mild intellectual disability

coarse facial features

short stature

webbing of the neck with low hairline

242
Q

How is Oculocutaneous albinism inherited?

A

Autosomal recessive

4 genes (TYR, OCA2, TYRP1, SLC45A2)

243
Q

What features are associated with oculocutaneous albinism?

A

General features

  • Hypopigmentation of hair, skin, iris (blue)
    • can see choroidal blood vessels in eyes
  • Infantile nystagmus, strabismus
  • Reduced visual acuity (from foveal hypoplasia)
  • With sun exposure
    • Rough/thickened skin (pachydermia)
    • Premalignant lesions (solar keratosis) and skin cancer
  • 4 different types with varying severity
244
Q

What types of genes are associated with Osteogenesis Imperfeca and how is it inherited?

A

Collagen gene

Autosomal dominant

245
Q

What are the features of Osteogenesis imperfecta?

A
  • Fractures
  • Conductive hearing loss in adulthood
    • because the middle ear bones break
  • Norma to short stature
  • joint hypermobility
  • dentinogenesis imperfecta (yellow, translucent teeth)
246
Q

What gene is associated with paramyotonia congenita and how is it inherited?

A

SCN4A gene

Autosomal dominant

247
Q

What are the features of paramyotonia congenita?

A

Myotonia

worse in the cold, stiff in the cold

248
Q

What kind of disorder in paramyotonia congenita and what tests can be done to test for it?

A

Channelopathy

Abnormal short exercise test

  • immediate drop that stays low

Normal long exercise test

249
Q

How is Parkinson disease inherited?

A

Idiopathic

Autosomal dominant

Autosomal recessive

X-linked

250
Q

What features are associated with Parkinson disease?

A

Resting tremor

muscle rigidity

Bradykinesia (slow movement)

shuffling gait and/or postural instability

depression, halluciations, dementia

Can lose sense of smell

251
Q

What genes are associated with Pendred syndrome and how is it inherited?

A

Mostly SCL26A4 gene, but can be FOX11 or KCNJ10

  • can be digenic
  • 48% have no mutation found

Autosomal recessive

252
Q

What features are associated with Pendred syndrome?

A

Congenital sensorineural hearing loss

  • enlarged or dilated vestibular aqueduct
    • Think Pendred if you see this
  • Mondini malformation possible

Thyroid goiters in early pubery to adulthood

253
Q

What features are associated with Pierre-Robin sequence?

A

Mandibular hypoplasia

U-Shaped cleft palate

big tongue

obstructive apnea (from tongue)

feeding difficulties

254
Q

What syndromes are associated with Pierre-Robein sequence?

A

Stickler

22q11 deletion

Treacher-Collins

Compomelic dysplasia

255
Q

What features are associated with Posterial Orthostatic Tachycardia (POTS)?

A

Dizziness

trouble standing up (because of blood vessel problems)

Tachyarrhythmias

(Treat with fluids and salts)

256
Q

What are the genetic causes of Prader-Willi syndrome?

A

Loss/alteration to the paternal copy of 15q11.2-q13

  • 70% from paternal deletion
  • Maternal UPD
  • Imprinting center defect (recurrence 50%)

Do methylation testing of SNRPN

257
Q

What features are associated with Prader-Willi syndrome?

A

Features

  • Severe hypotonia and feeding difficulties, FTT as an infant
  • Excessive eating & morbid obesity in early childhood
  • Global developmental delay, most need lifetime support and supervision
  • Temper tantrums, manipulative behavior, stubborn, OCD
  • Infertility, hypogonadism
  • Short stature, small feet and hands
  • Hypopigmentation of skin, eyes, and hair
  • Sleep abnormalities (daytime sleepiness)
  • Scoliosis, strabismus
  • Almond shaped eyes, thin upper lip, down-turned mouth, narrow nasal bridge
258
Q

What are the features of progressive familial intrahepatic cholestasis (PFIC)?

A

Liver problems

  • cholestasis (high direct bilirubin)
  • liver cancer
  • liver disease and failure
  • May been liver transplant

Itching

Growth failure

Pancrease, intestine, and lung problems

259
Q

What gene is associated with Psychosis, Pyrimidal Signs, and Macroorchism (PPM-X) and how is it inherited?

A

MECP2 gene

X-linked

260
Q

What are the features of Psychosis, Pyramidal Signs, and Macroorchism (PPM-X)?

A

Males

  • severe but not lethal
  • intellectual disability
  • resting tremor
  • ataxia
  • enlarged testes

Carrier females have milder symptoms

261
Q

What cancers are associated with Cowden syndrome?

A
  • Cowden syndrome-increased cancer risk
    • Thyroid cancer
      • Even in kids, get baseline ultrasound at age 5
    • Breast cancer
    • Uterine cancer
    • Other cancers
    • GI polyps, bleeding risk
    • Begin cancer screening at age 18
262
Q

What features are associated with Bannayan-Riley-Ruvalcaba syndrome (PTEN mutations)?

A

BRRS

  • Macrocephaly
  • Big baby at birth, normal height as adult
  • hypotonia
  • Mild intellectual developmental delay
  • Hamartomas
  • Speckled penis
  • Autism
    • 5-10% of children with macrocephaly and an autism spectrum disorder have a PTEN mutation
  • Intestinal polyposis (hamartomas)
  • Lipomas, hemangiomas
  • May have same cancer risks as Cowden syndrome
  • Screen for thyroid nodules
263
Q

How is Refsum disease inherited?

A

Autosomal recessive

264
Q

What are the features of Refsum disease?

A

Severe progressive sensorineural hearing loss

retinitis pigmentosa

anosmia

265
Q

How can Refsum disease be treated?

A

Dietary restriction of phytanic acid

high calorie diet

plasmaphoresis for cardiac arrhythmias or extremem weakness

266
Q

What gene is associated with retinoblastoma and how is it inherited?

A

RB1 gene

Autosomal dominant

  • 80% de novo, usually no family history
    • still test sibs in case germline mosaicism
  • If unilateral and no family history, 1 in 7 have a mutation

Test tumor tissue first if possible in case it is due to somatic mosaicism

267
Q

What cancers are associated with germline RB1 mutations?

A

Retinoblastoma

osteosarcoma

soft tissue sarcoma

brain tumors

nasal cavity tumors

268
Q

What gene is associated with Rett syndrome and how is it inherited?

A

MECP2 gene (loss of function mutation)

do deletin analysis

X-linked dominant

De novo mostly

lethal in males

269
Q

What surveillance do you do for RB1 mutations?

A

Eye exam every 3-4 weeks until age 1, then less frequently until age 3

Be aware of and evaluate bone pain or lumps for sarcoma risk

Unsure if this extra screening needs to be done for somatic mosaicism

270
Q

What are the features of Rett syndrome?

A

Features

  • Regression around 6 mos-1.5 years
  • Mental retardation
  • Language and learning disabilitys
  • Hand wringing
  • Lose the ability to walk
  • Parkinsonian-like symptoms

Neurodegenerative disorder

271
Q

What are the features of atypical Rett syndrome and what gene is it associated with?

A

Later regression than Rett

Similar to unconfirmed Angelman but with regression

Females can ahve few or no symptoms due to skewed X-inactivation

Can have just mild learning disabilities and neurological manifestations

MECP2 gene

272
Q

What are the features of ROHHAD?

A

Rapid onset obesity

Hypothalmic dysfunction

Hypoventilation and respiratory manifestations

Autonomic dysregulation

Behavior disorders

(very rare)

273
Q

What are the genetic causes of sickle cell disease and how is it inherited?

A

HbS variant (on beta-globin gene HBB) + another beta-globin gene mutation (SS, SC, SB+, SB0)

Autosomal recessive

274
Q

What is the sickle cell mutation and what is the carrier frequency?

A

HBB gene

Glu6Val

1 in 12 African Americans are carriers

1 in 625 Caucasians are carriers

275
Q

What are the features of sickle cell SS disease?

A

Features

  • anemia
    • Pallor
    • Delayed growth and puberty
  • Pain crises
  • Jaundice
  • Hand-foot syndrome (can’t bend hands & feet b/c of trapped RBCs)
  • Stroke
  • Acute chest syndrome (like pneumonia)
    • Fever, chest pain, hypoxia, and other respiratory symptoms
    • More common in kids, but can occur at any age
    • Most common cause of acute death in adults
    • Often follow vaso-occlusive crisis
  • General weakness
  • Priapism (erection won’t go away b/c of trapped RBCs)
  • Gallstones
  • Pulmonary hypertension
  • Chronic sores/ulcers on legs
  • Spleen dysfunction (splenomegaly) from sequestration and infarction
  • Infections (spleen fights infections)
  • Neurologic
    • Stroke, silent cerebral infarcts, cerebral hemorrhage, Moyamoya disease
276
Q

What treatment and management is done for sickle cell disease?

A
  • Prophylactic penicillin in children
    • illness can lead to an anemic crisis
  • prompt follow-up with fevers
    • risk for anemia
  • hydration
  • avoidance of climate extremes and extreme fatigue
  • Hydroxyurea
    • upregulates gamma chain production and fetal hemoglobin
  • bone marrow translplant for severe cases
277
Q

What are the most common causes of mortality in sickle cell disease?

A

In children

  • Infection
  • Splenic sequestration crises

In adults

  • Chronic end-organ dysfunction
  • Thrombosis
  • Treatment-related complications

Average lifespan 42y for males, 48 y for females

278
Q

What gene is associated with Simpson-Golabi-Behmel syndrome and how is it inherited?

A

GPC3 gene

X-linked

279
Q

What are the features of Simpson-Golabi-Behmel syndrome?

A

Overgrowth

mental retardation

dysmorphic features

hepatoblastoma risk

280
Q

What cancers are associated with SMARCB1 mutations?

A

Atypical/Tertoid rhabdoid tumor (AT/RT) (CNS rhabdoid)

Rhabdoid (can be in kidney or soft tissue

Schwanomatosis (multiple schwanomas)

281
Q

What are the genetic causes for SMARCB1 cancer risks?

A

Gonadal mosaicism common

Can be deleted with 22q11 deletion syndrome

282
Q

What should you think of when you see an Atypical/Teratoid rhabdoid tumor (AT/RT)?

A

SMARCB1

~35% of AT/RT are due to SMARCB1 mutations

283
Q

What should you think of when you see a rhabdoid tumor?

A

SMARCB1

~25% of rhabdoid tumors are due to SMARCB1

284
Q

What is the current screening for SMARCB1 mutations?

A

Baseline CNS MRI

renal ultrasound

285
Q

What gene is associated with Smith-Lemli-Opitz syndrome, what is the etiology, and how is it inherited?

A

DHCR7 gene

autosomal recessive

Cholesterol biosynthesis problem (high 7-DHC levels because it can’t be converted to cholesterol)

286
Q

What are the features of Smith-Lemli-Opitz syndrome?

A

Features

  • 2,3 toe syndactyly
  • Cleft palate
  • Cataracts
  • Intellectual disability
  • Hearing loss
  • Renal anomalies
  • Liver disease
  • GI problems (Pyloric stenosis, Hirschprungs)
  • Sex reversal in males
  • Microcephaly & midline defects (Dandy-Walker malformation, Holoprosencephaly)
  • Facial
    • Ptosis, Epicanthal folds, Downward slanting palpebral fissures
    • Small upturned nose
    • Micrognathia & High arches palate
  • Congenital heart defects (AVSD, ASD)
  • Abnormal Behavior
    • Sleep cycle disturbance
    • Self-injury
    • Autism behaviors (50% risk for autism spectrum disorder)
    • Depression
    • Hyperreactivity and temper dysregulation
287
Q

What does a quad screen for Smith-Lemli-Opitz look like?

A

Low uE3, HCG, and AFP

288
Q

How do you treat Smith-Lemli-Opitz syndrome and how effective is it?

A

Treat with cholesterol supplementation

Not super effective

289
Q

What are the genetic causes of Smith-Magenis syndrome and how is it inherited?

A

17p11.2 deletion

RAI1 is the critical gene

can also be RAI1 mutations

De novo

290
Q

What are the features of Smith-Magenis syndrome?

A

Features

  • Hypotonia, FTT, feeding difficulties
  • Infrequent crying as babies
  • Disrupted sleep pattern from abnormal circadian rhythm
  • Mild-moderate intellectual disability and developmental delay, significant expressive language deficit
  • Ocular abnormalities
  • Abnormal gait
  • Hearing loss or issues
  • Constipation
  • Hoarse voice and laryngeal anomalies
  • Self-injurious behavior and other behavioral problems
  • “Self hug”
  • scoliosis
  • short stature
  • small hands and feet
  • Facial
    • tent shaped upper lip
    • upslanting palpebral fissures
    • hypopigmentation with rosy cheeks
    • synophrys
291
Q

What kind of disorder is Sodium Channel Myotonia?

A

Channelopathy

292
Q

What are the features of sodium channel myotonia?

A

Grip myotonia

electrical myotonia

episodic weakness

muscle pain

symptomatic eyelid myotonia

normal short and long exercise tests

293
Q

What are the genetic causes of Spinal Muscle Atrophy (SMA)?

A

SMN1 gene

  • majority due to a homozygous deletion of exon 7
  • some compound heterozygotes of an exon 7 deletion and an intragenic mutation

SMN2 can provide a better outcome

  • the more copies of SMN2 you have, the milder the phenotype
294
Q

What are the features of spinal muscle atrophy (SMA) and what is the prognosis?

A

Severe muscle weakness

  • In the severe form (Type 1-most common), they may never sit on their own
  • In the least severe forms (Type 3 and Type 4), they may be able to walk or just have mild proximal muscle weakness

Respiratory and bulbar muscle weakness with swallow dysfunction

  • may need a G-tube
  • leads to aspiration and pneumonia
  • Usually die <2 years due to respiratory and swallowing issues

Develop REM sleep disordered breathing and eventually NREM sleep disordered breathing

With the less severe forms, may have tremors, contractures, kyphoscoliosis, obesity, scoliosis

295
Q

What gene is associated with spinocerebellar ataxia and how is it inherited?

A

ATXN gene

Autosomal dominant with anticipation

Trinucleotide repeat

  • CAG repeats with effect from interrupting CAT repeats
    • 6-44 CAG repeats is normal
    • 36-44 repeat pathogenicity depends on CAT size
      • If no CAT interruptions, you are asymptomatic but can expand into pathogenic range for children
      • 39-44 repeats without CAT interruptions can be symptomatic, but if interrupted may be asymptomatic
    • >44 repeats is pathogenic
296
Q

What are the features of spinocerebellar ataxia?

A

Features

  • Progressive cerebellar ataxia
    • Chorea, distal muscle weakness, peripheral neuropathy, gait disturbance
  • Deterioration of bulbar functions
    • Dysarthria, dysphagia
  • Other
    • Nystagmus, optic atrophy, brisk deep tendon reflexes, hypotonia

Supportive care only

  • Onset to death 10-30 years
297
Q

What genes are associated with Stargardt disease and how is it inherited?

A

ABCA4 gene, autosomal recessive

EVOLVL4 gene, autosomal dominant

298
Q

What are the features of Stargardt Disease

A

Eye problems with a heterogeneous presentation (60% present <40 years)

  • Hereditary macular dystrophy
  • progressive worsening of visual acuity
  • retinitis pigmentosa
299
Q

What gene is associated with Stickler syndrome and how is it inherited?

A

COL2A1 gene

Autosomal dominant

300
Q

What are the features of Stickler syndrome?

A

Features

  • Myopia from birth–>thick glasses
  • Retinal detachment
  • Mitral valve prolapse
  • Hypermobile joints
  • Progressive sensorioneural hearing loss
  • Later develop spondyloepiphyseal dysplasia
    • Leads to arthritis
  • Mild short stature
  • Narrowed joint spaces on x-ray
  • Abnormalities of the vitreous gel architecture (ocular finding)
    • Pathognomonic
  • Facial features
    • Flat midface
    • Depressed nasal bridge with short nose
    • Anteverted nares
    • Micrognathia
    • U-shaped cleft palate from Pierre Robin sequence

Can be confused with Marfan

301
Q

What are some things you should ask about when you suspect Stickler syndrome?

A

Early arthritis (from spondyloepiphyseal dysplasia)

Retinal detachment

Cleft palate

Hearing loss

302
Q

What is the inheritance of strabismus?

A

Multifactorial and complex Mendelian genetics

Strong familial component for syndromic and non-syndromic forms

303
Q

What is the recurrence risk to sibs for strabismus?

A

20-30% if the parents are not affected

30-50% if a parent is affected

304
Q

What is the risk for strabismus in a FDR and a SDR of an affected person?

A

16-50% recurrence risk for FDR

~8% risk for SDR

305
Q

What gene is associated with Sturge-Weber syndrome and how is it inherited?

A

GNAQ gene (548G>A)

  • Activation of the ERK pathway

Not seen familialy!

  • 1-18% are somatic mosaics
306
Q

What are the features of Sturge-Weber?

A

Vascular problems

  • Port-wine stains on face
  • seizures
  • mental retardation

Glaucoma

Calcifications to the cortex

307
Q

What do problems with surfactant protein C cause?

A

Interstitial Lung Disease

  • misfolded surfactant protein C accumulates in the alveolar type II cells and results in cell injury and apoptosis
308
Q

What is the prevalence of Factor V Leiden?

A

3-5% of Caucasians are heterozygous

1 in 400 caucuasians are homozygous

12-20% of unselected venous thrombosis patients have a Factor V Leiden mutation

309
Q

What factors play a role in clot formation?

A

Virchow’s Triad

  • Changes in the vessel wall
  • Changes in blood composition
  • Changes in blood flow

Environment

  • oral contraceptives, hormone replacement therapy
  • pregnancy
  • weight, diet

Genetics

310
Q

What are the symptoms of thrombosis?

A

Pain, tender to the touch

tight

swelling

redness

311
Q

Should you test for thrombophilia conditions?

A

It’s not really recommended

  • Knowing about a genetic mutation will not change management

But testing might increase awareness

Do an individual assessment to decide to test or not

312
Q

What risks are associated with Prothrombin mutations?

A

2-3 fold increased risk for thrombotic event

slightly increased risk for arterial clots (stroke, heart attack)

Associated wtih pregnancy loss and pregnancy complications

313
Q

What is the prothrombin mutation associated with an increased risk for a thrombotic event?

A

Prothrombin G20210A

314
Q

What is a homozygous deficiencty of Protein C or Protein S associated with?

A

Neonatal purpura fulminans

Severe

315
Q

What risks are associated with Protein C and S deficiencies?

A

2-10 fold increased risk for thrombosis (5-10% lifetime risk)

  • Rate of recurrence slightly increased

Mild assosication with stroke and heart attack, especially in young

Associated with pregnancy loss (especially late)

Treat with human plasma-derived protein C concentrate

316
Q

What risks are associated with Antithrombin II deficiency?

A

50% lifetime risk to clot

  • VTE risk is 10-17% per year

Weak association with MI/stroke

Slightly higher risk of fetal loss

Homozygous is lethal

Heterozygous is rare

317
Q

What gene is associated with Treacher-Collins syndrome and how is it inherited?

A

TCOF1 gene

Autosomal dominant

60% de novo

318
Q

What are the features of Treacher-Collins syndrome?

A

Underdevelopment of bone in the face and jaw

  • very dysmorphic
  • downslanting palpebral fissures

Conductive hearing loss because of external ear abnormalities

Coloboma of the lower eyelid

Pierre-Robin sequence

319
Q

What genes are associated with tuberous sclerosis and how is it inherited?

A

TSC1 and TSC2

Autosomal dominant

2/3 de novo

320
Q

What are the features of tuberous sclerosis?

A

Very variable, may not be affected at all

Skin

  • Ash leaf spots/hypopigmented spots
  • Shagreen patch (looks like rash)
  • Facial angiofibroma (looks like acne)
  • Ungual fibroma (fibroma under the nail)

Kidney issues

  • Can be associated with polycystic kidney disease (TSC2)
  • Benign angiomyolipoma (huge mass on kidney, cysts)

Brain issues

  • Subependymal glial nodules
  • Cortical/subcortical tubers
    • 70%
    • Correlated with seizures

Cardiac rhabdomyoma

  • Infants and fetuses only
  • Typically goes away and is benign

Dental pits

Lymphangioleiomyomatosis (large growth in the lung)

  • Famales only

Seizures

Developmental delays

Headaches

321
Q

What disorder should you think of when you see a cardiac rhabdomyoma?

A

Tuberous sclerosis

322
Q

How is tuberous sclerosis managed?

A

Management

  • MRI 1-3 years
  • Seizure management with meds, removal of tubers, electroencephalography
  • Electrocardiogram & ECG if heart problesm
  • Renal u/s
  • Ophthalmology exam
  • Neurodevelopmental & behavioral evaluation
  • Chest CT for adult females (for LAMs)
323
Q

What is the genetic cause of Turnder syndrome?

A

XO genotype

  • 50% mosaic
    • If are mosaic XY, have a 12% risk for gonadoblastoma
324
Q

What are the features of Turner syndrome?

A

Features

  • Short stature
  • Phenotypic female
  • Infertility/don’t undergo puberty/premature ovarian failure
  • Webbed neck
  • Low posterior hairline
  • Lymphedema of hands and feet
  • Skeletal abnormalities
  • Kidney issues
  • Heart defects (aortic coarctation)
  • Variable developmental delay and behavior problems
325
Q

What kind of disorder is Pompe disease?

A

Glycogen storage disorder (Type II)

and a lysosomal storage disorder

326
Q

What gene is associated with Pompe disease and how is it inherited?

A

GAA gene

Autosomal recessive

327
Q

What are the features of Pompe disease?

A

Features

  • Muscle weakness
  • Cardiomyopathy
  • Delays
  • Failure to thrive
  • Respiratory distress
  • Early death (if infantile presentation)
328
Q

How is Pompe disease treated and what does it improve?

A

ERT available

  • Increases lifespan
  • Improves myocardial function
  • Improves skeletal muscle function
  • Improves motor abilities & walking abilities (from improving muscle function)
  • Helps with sleep disordered breathing and lung function
  • Improves quality of life
329
Q

How is Usher syndrome inherited?

A

Autosomale recessive

330
Q

What are the features of Usher syndrome?

A

Sensorineural hearing loss

  • Mostly congenital
  • May not develop speech without cochlear implant

Retinitis Pigmentosa

  • Progressive vision loss
  • Onset usually in 1st to 2nd decade of life
331
Q

How does retinitis pigmentosa present?

A

Loss of night vision

Loss of peripheral vision

–>tunnel vision

332
Q

What causes VACTERL?

A

Inheritance unknown

Multigene and environement association

Associated with maternal diabetes

333
Q

What is the recurrence risk for VACTERL?

A

2-3%

334
Q

What are the features of VACTERL?

A

Features (at least 3+ of the following)

  • Vertebral abnormalities
    • hypoplastic/malformed vertebrae & ribs, scoliosis, sacral agenesis
  • Anal atresia
    • can’t poop, passageway not there
  • Cardiac defect
    • VSD mostly, can be ASD, tetralogy of fallot, CHF, hypoplastic left heart, truncus arteriosus
  • Tracheo-Esophageal fistula and/or esophageal atresia
    • leads to aspiriation, respiratory infections, FTT
  • Renal abnormalities
    • renal aplasia, dysplasia, hydronephrosis etc
  • Limb anomalies
    • radial aplasia/hypoplasia, absent/displaced thumb, poly/syndactyly, clubfoot
335
Q

What gene is associated with Von Hippel-Lindau disease and how is it inherited?

A

VHL gene

Autosomal dominant

336
Q

What is associated with VHL Type 1?

A
  • Retinal hemangioblastoma
  • CNS hemangioblastoma
  • Clear cell renal cell carcinoma
  • Pancreatic neoplasms & cysts
  • Deletion/truncating mutation
337
Q

What is associated with VHL Type 2?

A

Type 2A

  • Pheo
  • Retinal hemangioblastomas
  • CNS hemangioblastomas

Type 2B

  • Pheo
  • Retinal hemangioblastomas
  • Clear cell renal cell carcinoma
  • Pancreatic neoplasm cysts

Type 2C

  • Pheos only
338
Q

What risk is associated with Von Willebrand disease and what are the symptoms?

A

Bleeding tendency (milder than hemophilia)

Symptoms

  • Menorrhagia
  • Epistaxis
  • Bleeding at dental extraction or with minor injury
  • Ecchymoses
  • Post-operative hemorrhage
339
Q

What type of Von Willebrand disease is most common?

A

Type 1 (75%)

340
Q

What kind of defect is Type 1 Von Willebrand disease?

A

Quantitative defect of Von Willebrand factor (not enough factor made)

341
Q

How is Von Willebrand disease inherited?

A

Mostly autosomal dominant except for Type 2N and Type 3 (autosomal recessive)

342
Q

What are the features of Von Willebrand disease Type 1?

A

Mild to moderate mucocutaneous bleeding

reduced Factor VIII (because they bind togeher)

343
Q

What kind of defect is Type 2 Von Willebrand disease?

A

Qualitative problem of Von Willebrand factor (can’t function or bind as it should)

344
Q

What type of Von Willebrand disease mimics hemophilia A and how is it inherited?

A

Von Willebrand disease Type 2N

autosomal recessive

Excessive bleeding with surgery

345
Q

What are the features of Type 3 Von Willebrand disease and how is it inherited?

A

Hemophilia phenotype

  • severe, recurrent, spontaneous mucocutaneous and musculoskeletal bleeing

Autosomal recessive

  • homozygous form of Type 1 Von Willebrand disease
  • No Von WIllebrand factor is made

May develop Von Willebrand Factor inhibitors

346
Q

How is Waardenburg syndrome inherited?

A

Autosomal dominant mostly

some autosomal recessive

347
Q

What are the features of Waardenburg syndrome?

A

Sensorineural hearing loss (variable degree)

White forelock

Heterochromia irides

Dystopia canthorum (wide spaced eyes)

Hirschprung disease

348
Q

What is the genetic cause of WAGR syndrome?

A

Deletion of WT1 and PAX6

349
Q

What are the features of WAGR syndrome?

A

Wilms tumor

Aniridia

Genitourinary abnormality

mental Retardation

350
Q

What gene is associated with Wilson’s disease and how is it inherited?

A

ATP7B gene

Autosomal recessive

351
Q

What is the cause/etiology of Wilson’s disease?

A

Copper accumulation in the eyes, brain, and kidneys

Low serum copper, higher urine copper

352
Q

What are the features of Wilson’s disease?

A
  • Acute or chronic liver failure
  • Neurologic disease
    • due to copper accumulation in the brain
    • change in school performance or behavior
  • Kayser-Fleischer rings
    • due to copper accumulation in the eyes
353
Q

What should be done for the family when someone is diagnosed with Wilson’s disease?

A

Screen all FDR for Wilson’s disease (urine and serum test, look for Kaiser-Fleischer rings)

354
Q

What is the treatment for Wilson’s disease?

A

Chelation to try to prevent the accumulation of copper

355
Q

What is the genetic cause of Wolf-Hirschhorn syndrome and how is it inherited?

A

4p16.3 deletion

85-90% de novo

356
Q

What is the female:male ratio for Wolf-Hirschhorn syndrome?

A

2:1 female:male

357
Q

What are the features of Wolf-Hirschhorn syndrome?

A

Features

  • “Greek warrior helmet” face, hypertelorism, microcephaly, asymmetry
  • Poorly formed ears
    • Hearing loss
    • Pits or skin tags
  • Intellectual disability mild to severe
  • Developmental delays
    • Poor motor and verbal skills
  • Hypotonia, feeding difficulties
  • IUGR and postnatal growth retardation
  • Febrile seizures
  • Hemangiomas (red spots)
  • Marble/dry skin
  • Skeletal anomalies
    • Scoliosis, short stature
  • Congenital heart defect
  • Antibody deficiency
358
Q

What is the prognosis for Wolf-Hirschhorn syndrome?

A

May be stillborn

35% die within first 2 years

Can live into 20s-40s

359
Q

What type of genes are associated with Zellweger syndrome and how is it inherited?

A

Genes that make up the peroxisome

Autosomal recessive

360
Q

What is the cause/etilogy of Zellweger syndrome?

A

Defect with perosisomal metabolism

  • Leads to the accumulation of very long fatty acids and branched chain fatty acids, and a deficiency of plasmoalogens
361
Q

What are the features of Zellweger syndrome?

A

Features

  • Hypotonia, poor feeding
  • Seizures
  • Apnea
  • Hepatomegaly and/or renal cysts
  • Vision problems
  • Chondrodysplasis punctata
  • Brain issues
    • Impaired neuronal migration and positioning
    • Demyelination of CNS (cerebral neurons)
    • Reduced brain development
  • Progressive vision and hearing loss
  • Profound developmental delay/intellectual disability
  • Facial
    • High forehead
    • Hypoplastic supraorbital ridges
    • Epicanthal folds
    • Midface hypoplasia
  • Heart defects (VSD, ASD)
  • Eventually respiratory distress, GI bleeding, and liver failure
362
Q

How do you test for Zellweger syndrome?

A

Start with a biochemical test for very long chain fatty acids, branched chain fatty acids, and plasmalogens

363
Q

What is the prognosis for Zellweger syndrome?

A

Survival usually <1 year

Genetic disorders (2 decks)

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