Genetics/Syndromes Flashcards
CHARGE
CHARGE syndrome.
CHD7 gene- most sporadic
C (coloboma)
H (congenital heart defects)
A (choanal atresia)
R (retardation of growth/developmental)
G (genital anomalies)
E (ear anomalies or deafness.)
VACTERL association
VACTERL
- Due to disruption in early embryogenesis
V (vertebral defects)
A (anal atresia)
C (cardiac defects)
T (tracheo-oesphageal defects)
R (renal anomalies)
L (limb abnormalities.)
Rubenstein-Taybi
Microdeletion chromosome 16
- Short stature
- Mod-severe ID
- Broad fingers/toes gap
- Facial features as per pic
DiGeorge
CATCH22
2q11.1 deletion syndrome
C- heart defects
A-
T- Thymic hypoplasia, absent T/B cells
C- Cleft palette
H- Hypocalcemia
poor immune system function, cleft palate, hypocalcaemia and delayed development.
Loeys-Dietz
AD/75% de novo
SMAD3, TGFB
Overview: cardiac aneurysms, joint laxity, bifid uvula
Aneurysms/dissections
Pectus excavatum/carinatum, scoliosis, joint laxity,arachnodactyly/talipes, C-spine malformations
BIFID UVULA, wide spaced eyes, craniosynostosis
Skin: translucent/easy bruising
Homocysteinuria
AR- CBS mutation, intermediate in methionine → cysteine
Overview: joint contractures, inferior lens dislocation, low IQ, stroke risk
B6 responsive (mild/unresponsive)
Ectopia lentis (downward), tall stature/long limbs, pectus, scoliosis, CVA/VTE, dev delay/ID
Ix: elevated total homocys/met
Rx: B12/folate, met restricted diet
Marfans
AD, FBN1 gene, 25% denovo
Overview: joint laxity, superior lens dislocation, normal IQ
Ectopia lentis (sup) 50-80%
Aortic root dilatation/MVP/TVP
Skeletal overgrowth, arachnodactyly, joint laxity, scoliosis
High arched palate, retrognathia
N IQ
Score: Ghent criteria >7 to diagnose
Shprintzen-Goldberg syndrome
Craniosynostosis
Narrow head, hypertelorism, high arched palate, micrognathia, Marfanoid body habitus
Delayed development/ID
Poor tone, umbilical hernias
Types of genetic tests overview
Chromosomal testing
- Cytogenetics: karyotype
- Molecular cytogenetics: microarray, FISH, MLPA
Imprinting
- DNA methylation studies
Known mutations
- Single gene analysis
- SNP array
- MLPA
Unknown mutations
- NGS, WES, Sanger sequencing (slow)
Trinucleotide repeat analysis
- For TNA disorders i.e DMD, FXS
- Amplify DNA then Southern blot
When to use different genetic tests
Gene defects
- Microarray: duplications or deletions, unbalanced/microdeletions
- Karyotype: aneuploidies, sex chromosomes, translocations
- SNP array (single nucleotide polymorphisms): consanguinuity/wide genome screen
- FISH- microdeletions/duplications, need to have idea of gene that youre looking for
- MLPA- PCR amplification in area of interest- small deletions/duplications
Imprinting/TNA:
- Triplet repeat analysis: PCR then southern blot
- Methylation studies: UPD (if neg = imprinting)
Unknown
- NGS, WES
Other:
-Chromosomal breakage test: Fanconi, hereditary spherocytosis, AT
What do S,N,W Blots look for?
Blots (SNoW DRoP)
Southern = DNA
Northern = RNA
Western = Protein
Broad genetic screening tests- types of sequencing?
Sanger sequencing: screening for unknown mutation
Whole exome sequencing (WES)
- Exons (coding regions)
- Slower than targeted panels
- Can identify genes responsible for pathology
Next Gen Sequencing/whole genome
- All genes, translocations and non-coding DNA
- Cannot detect triplet repeats pr methylation defects
Types of cytogenetics, method and role?
Cytogenetics
Can identify: aneuploidies, large chromosomal imbalances, balanced/unbalanced translocations
(NOT- single gene, microdeletions, triplet repeat, imprinting)
Karyotype: directly analyses whole chromosomes
- Used for trisomies/monosomies- T21, Klinefelter/Turner
Molecular cytogenetics
Microarray
Can identify: gains/losses in genetic material
- CGH: compares DNA from 2 sources
- SNP: compares to control, can detect heterozygosity (more information)
uses: microdeletion/dup, single gene diagnoses
FISH
Can identify: presence/absence of DNA sequences on chromosomes, balanced rearrangements, localisation of DNA targets
i.e Trisomy, microdup/del- DiGeorge, Williams
MLPA
Can identify: duplication/deletions- amplifies DNA and seperates based on size
Klinefelters- 47XXY
Non-disjunction of X chromosome in meitotic division
1 in 800-1000 males
More common than turners
Breast tissue, wide hips, & euchanoid habitus- increased height/clinodactyly, reduced muscle bulk
Reduced libido/decreased fertility, testes smaller, may have hypogonadism
Language disabilities/ADHD, shy/depression
55% MVP
Ocular albinisim OA1
X-linked disorder
- Limited eye disease
- Poor vision/nystagmus
- Mums (carrier) may also have ocular albinism/mosaicism
Tietz syndrome
-MITF gene mutation (also seen in Waardenburg)
- Heterochromia/greying of hair
- Pale blue eyes/blonde hair
- Congenital deafness
- Hair colour may change
Waardenburg syndrome
- Heterchromia, white forelock
- SNHL with normal external eat
Jervell-Lange-Neilsen
Deafness/SNHL & long QT
Usher syndrome
SNHL & normal external ear
Retinitis pigmentosa
Pendred syndrome
SNHL, normal external ear
Hypothyroidism
Alport syndrome
COL2
Haematuria/nephritis
SNHL & normal external ear
Anterior chamber eye abnormalities
Chediak-Higashi Syndrome
Disorder of vascular trafficking (AR) Partial oculocutaneous albinism
Recurrent pyogenic infections
- Will develop HLH
Coagulopathy
Neurological abnormalities
Ix: giant cytoplasmic granules in leucocytes/platelets - pathognominic
Rx: HSCT- does not fix eye/skin/neuro abnormalities
Vici syndrome
-Congenital agenesis of the corpus callosum
- Bilateral cataracts
- Hypopigmentation of skin and hair
- Cardiomyopathy
- Immunodeficiency
Griscelli syndrome
Disorder of vascular trafficking (AR)
RAB27a gene
- Sparse/hypopigmented hair
Oculocutaneous albinism - Neutropenia
- NO giant granules
Hermansky-Pudlak syndrome
AR
Oculocutaneous albinism
Visual impairment
Platelet dysfunction and prolonged bleeding
Abnormal storage of a fatty-like substance (ceroid lipofuscin
Norrie Disease
X linked
- Microcephaly
- Bilateral retinal dysplasia
- Neuropsychiatric symptoms.
Incontinentia Pigmenti
X-linked recessive (lethal in males, only females affected)
- Skin lesions (hypopigmented initially)
- Retinal dysplasia
Inheritance patterns
- Autosomal dominant
Males and females
Every affected person has at least one affected parents
3/4 children affected
Inheritance patterns
- Autosomal recessive
Increased in consanguinity
Males and females
Parents not affected (carrier 1/4)- skips a generation
Inheritance patterns
- X-linked dominant
Mum to all sons
Males often die/females affected
All daughters of affected male will receive gene
Inheritance patterns
- X-linked recessive
Mum to all sons
Females NOT affected
All daughters of affected male will receive gene
Inheritance patterns
- Translocation
Phenotypically normal carrier with increased risk of miscarriages or abnormal offspring (both males and females)
Reciprocal: break into two parts and exchange
Robertsonian: fusion of two short arms near centromere (45 not 46)
Inheritance patterns
- Imprinting
Gene expression depends on which parent the chromosome came from
- Maternal imprinting = maternal gene silenced (pat expressed)
- Paternal imprinting = paternal gene silencing (mat expressed)
Occurs during gametogenesis/embryonic development
Inheritance patterns
- Triplet repeat
Disease becomes more severe as generations go on
(greater expansions with each inheritance)
- I.e Fragile X, Huntington, Myotonic dystrophy, spinocerebellar ataxia
Inheritance patterns
- Mitochondrial
Mum affected, passes on to both sexes
Inheritance patterns
- Mitochondrial
Mum affected, passes on to both sexes
Autosomal dominant with incomplete penetrance
Males and females
Can skip a generation but sometimes transmitted
Meier-Gorlin syndrome
ORC1 gene: short stature, microcephally, micrognathia, under-developed or absent patella and small ears.
Pierre Robin sequence
- Micro/retrognathia, mandibular hypoplasia
- Glossoptosis
- Cleft palate WITHOUT cleft lip
Rx: prone positioning, NGT feeds/NPA, surgical distraction if severe
Miller Syndrome
Malar hypoplasia, micrognathia, cleft lip and cleft palate and downward slanting eyes
Duane Syndrome
Sporadic, some AD
Congenital strabismus
L) > R) eye
Type 1 = difficulty with abduction (one D in abduction)
Type 2 = difficulty with adduction (two Ds in adduction)
Type 3 = difficulty with both (3 Ds in abduction and adduction).
80% of cases are type 1
Associations: Klippel-Feil anomaly and hemifacial microsomia
Goldenhaar/Hemifacial microsomia
1 in 5,000
- Unilateral orbit, ear, facial muscle &mandible hypotrophy
- Microtia/hearing loss
- Epibulbar dermoids (eye)
Townes-Brocks
SALL1 gene TCOF1 gene
- Dysplastic ears
- Imperforate anus
- Malformed thumbs
Treacher-Collins
TCOF1 gene
- Midface hypoplasia
- Cleft palette
- Ear & eye abnormalities
Pendred syndrome
Iodine transport mediated by pendrin
= giotre + SNHL
- Usually no thyroid dysfunction, may have mild hypothyroidism
NF1
Autosomal dominant, 50% sporadic
Chr 17
> 6 cafe au lait
2 lisch nodules
axillary freckling
optic glioma
2 neurofibroma/1x plexiform neurofibroma
Osseous lesions
+ve FHX
NF2
Autosomal dominant, 50% sporadic
Chr 22
Bilat acoustic neuroma
Meningiomas
Cataracts
+ve FHX
Tuberous Sclerosis 1/2
Autosomal dominant, 75% sporadic
> 3 ash leaf spots
2 ungal fibromas
2 angiomyolipomas
Shagreen patch
Retinal harmatoma
Cardiac rhabdomyoma
Cortical dysplasia
Subependymal nodules/astrocytoma
Minor: Confetti skin lesions, dental pits, renal cysts, fibromas
Diagnosis?
Williams
Autosomal dominant
7q11 del- ELN gene
‘Elfin facies’ with cocktail personality
Hypercalcemia
Supravalvular AORTIC/peripheral pulmonary stenosis (AS only if ELN point mutation)
Developmental delay/ID
Diagnosis?
Alagille
Autosomal dominant
JAG1/NOTCH2
Short, triangular face
Butterfly vertebrae
Peripheral pulmonary stenosis
Ix: PAUCITY OF BILE DUCTS on Bx, conjugated hyperbilirubinemia
Prone to Moya Moya disease
Marfan’s
Autosomal dominant- FBN Ch15
Arm span >height, tall, joint hypermobility
MVP/aortic aneurysms, ectopia lentis (upward), learning disability
Ehlers Danlos
Autosomal dominant
COL5A
Tall, joint hypermobility
Easy bleeding, berry aneurysms, aortic root dilatation
Diagnosis?
Osteogenesis imperfecta
Autosomal dominant COL 1A1/2
High ALP, hypercalciuria
Short stature
Blue sclera, opalescent teeth
Hearing loss and poor vision
Type 1- mild
Type 2- lethal
Type 3- progressive
Type 4- moderate
Diagnosis?
Stickler Syndrome
Autosomal dominant- COL2A1
Cleft palete, PRS (hypoplasia mandible, glossoptosis)
MVP, joint hypermobility
SNHL
Diagnosis?
Brachio-oto-renal syndrome
Autosomal dominant- EYA1
Pre-auricular pits/tags, microtia
SCM sinus/cyst
Renal malformations
Diagnosis?
Diamond Blackfan Anaemia
Autosomal dominant
Triphalangeal thumb/absent thumb
Cataracts
Anaemia with low RCC, fatty BM
- Cx: AML
Diagnosis?
Von Hippel Lindau Syndrome
Autosomal dominant- VHL Chr3
Multiple renal, liver, endocrine tumors
Diagnosis?
Cornelia De Lange Syndrome
Autosomal dominant- NIBPL, SMC1A, most sporadic
Monobrow (synophyrys), hirstutism, short/upturned nose
ASD/VSD
ID
Diagnosis?
Waardenburg Syndrome
Autosomal dominant
Pale blue eyes, white forelock
SNHL/vision loss
Diagnosis?
Costello Syndrome
Autosomal dominant- RASMAPK/HRAS
Big babies, loose skin on hands, deep palmar crease
FTT
Rhabdomyosarcoma/neuroblastoma
Diagnosis?
Noonan Syndrome
AD- RASMAPK/ PTPN11/SOS1, sporadic
Widely spaced nipples/sternal anomaly
Pulmonary stenosis (supravalvular), ASD, HOCM
Associated malignancies- JMML
Diagnosis?
Cardiofasciocutaneous syndrome
Autosomal dominant- RASMAPK KRAS (similar to noonans)
Sparse curly hair, ID/dev delay
Seizures
HOCM
Diagnosis?
Treacher-Collins Syndrome
Autosomal dominant
- Midface hypoplasia
- Microtia/SNHL
- Cleft
A1AT Deficiency
Autosomal dominant
Defective A1AT builds up in lung
- Neonatal jaundice, pale stools & hepatomegaly- cirrhosis/renal failure (first 1-2yrs)
- Emphysema (panacinar/LL), chronic bronchiectasis- damage due to neutrophil elastase
Heterozygote: PiMZ = 60% function
Homozygote: PiZZ = 10-20% function- less likely to have liver disease
Biopsy: PAS+ve/diastase resistant
Achondroplasia
Autosomal dominant
FGFR3, most sporadic
Inhibits chondrocyte development
Rhizomelic dwarfism
OSA/AA instability
Diagnosis?
Apert
Autosomal dominant/sporadic
Craniosynostosis, exopthalmos, cleft palette, syndactyly
Mod ID
Diagnosis?
Crouzon
Autosomal dominant
Craniosynostosis, hydrocephalus, proptosis, strabismus
Normal intelligence, normal hands & feet
Diagnosis?
ADPKD
Autosomal dominant- Chr 4
Bilateral, large cystic kidneys
Multiple cysts throughout abdomen
Haematuria
Familial Adenomatous Polyposis
Autosomal dominant
Multiple colonic polyps
+ve FHx- suggest yearly scope from 10y
Li Fraumeni
Autosomal dominant
Multiple malignancies
- Sarcoma
- Breast cancer
- Adrenal Ca
- Leukemia
MEN1, MEN 2A & B
Autosomal dominant
Charcot-Marie-Tooth
Autosomal dominant
PMP2 (60%)- demyelinating, MFN2 (30%)- axonal
Peripheral neuropathy, foot drop
Motor > sensory
Normal CK
‘Onion bulb’ appearence on nerve Bx
CHARGE
Autosomal dominant
Coloboma
Heart defects- tetralogy of Fallot
Atresia
Retardation (mental)
Genital abnormalities
Diagnosis?
Hypomelanosis of Ito
Autosomal dominant
- Associated with seizures & developmental/cognitive delay
Diagnosis?
Osler-Weber-Rendu (HHT)
Autosomal dominant
Skin lesions- cherry angiomas
GI bleeding/epistaxis/haematuria
AVMs
Gilbert
Autosomal dominant
- Glucoronyltransferase
- Unconjugated hyperbilirubinemia
- Intermittent jaundice
Diagnosis?
Peutz-Jeghers
Autosomal dominant
Risk of intestinal polyps & malignant transformation
Myotonic dystrophy
Autosomal dominant
MD1 = DMPK
- GTG triplet repeat
- Anticipation- maternal
Myotonia (unable to relax muscles after action)
Muscle wasting
Cataracts
Cognitive delay
Huntingtons
Autosomal dominant
- CAG triplet repeat
- Anticipation-paternal
Depression, choreiform movements/hemiballismus, caudate atrophy
Diagnosis?
Types?
CF
Autosomal recessive
Type 1- no protein G,W,R
Type 2- cant fold (delF508)- F,N,I most common, Rx Lumicaftor
Type 3- cant transport G551D - G,S,V - Rx Ivacaftor
Type 4- decreased function- R117H, asymptomatic
Dx?
Wilson disease
Autosomal recessive - ATP7B
<10y Liver/abdo Sx
>10y Abnormal movements/psychiatric disease
Fanconi Anaemia
Autosomal recessive
FANCA/B
BM failure
Abnormal thumbs/radial aplasia
Short stature
Cafe au lait macules/ash leaf spots
CHD- PDA, ASD/VSD, situs inversus
Ix: high HbH, AFP, pos chromosomal breakage study
Homocysteinuria
Autosomal recessive
Like Marfans but
Low IQ
Downward ectopia lentis
Coagulopathic
Dx?
ARPKD
Autosomal recessive
Bilateral smaller cysts in kidneys
Potter’s sequence= oligohydramnios
- DDH/talipes
- Pulmonary hypoplasia
Flank mass, renal & liver dysfunction
Bartter/Gitelman
Autosomal recessive
Bartter: N/K/Cl cotransporter DLH (frusemide)
- Hypokalemic/chloremic acidosis
- Stones
- Low Na/K+/Cl
- High urine Ca
Gitelman: Na/K transport DCT (thiazide)
- Low Mg2+, muscle cramps, polyuria
- Low K+, acid, high glucose/uric acid
- Low urine Ca
Glanzman Thrombasthenia
Autosomal recessive
Normal platelet number
Gp2b1a defective
Unable to aggregate
Dx?
Smith-Lemli-Opitz
Autosomal recessive
- Cholesterol synthesis problem
- Poor growth
- Cleft palete
- Cataracts
- ID
- Absent corpus callosum
Cartillage-Hair-Hypoplasia
Autosomal recessive
- Dwarfism
- Sparse hair
- BM failure & increased risk of malignancy
Carpenter
Autosomal recessive
- Craniosynostosis
- Fusion of fingers
- Situs inversus
- SNHL
Ataxia-Telangectasia
Autosomal recessive
- Ataxia/nystagmus
- Telangectasia
- Recurrent sinopulmonary infections
Ix: high AFP, low IgA, lack of ATM protein on Western blot
Metachromatic Leukodystrophy
Autosomal recessive
Hypotonia, distal weakness, absent reflexes
SMA
Autosomal recessive
- Lack SMN1 protein
- Anterior horn - LMN signs, areflexia, decreased tone, fasciculation
Type 1 = most severe, never sit
Type 2 = intermediate, never stand
Type 3 = shoulder girdle
Normal CK
Bx: large gap atrophy
Tay-Sachs
Autosomal recessive
Sphingolipid accumulation
Cherry red spots in macula
TAR (thrombocytopenia absent radii)
Autosomal recessive
Freidrich’s ataxia
Autosomal recessive
- Ataxia, weakness- distal
- Vision/speech/hearing changes
- HOCM
- high plantar arches
Crigler Najjar
Autosomal recessive
Type 1 = severe lifelong jaundice rx transplant
Type 2 = less severe
Kartageners/PKD
Autosomal recessive
Bronchiectasis
Infertility
Situs inversus
Gluc-galactose malabsorption
Autosomal recessive
- Severe osmotic diarrhoea, improves when milk stopped
- Renal calculi
Ix: hydrogen breath test
Rx: fructose only formula/sugar
Congenital chloride diarrhoea
Autosomal recessive
Dehydration
Low Cl/stool Cl high ++
PKU
Autosomal recessive
Pale hair, blue eyes, eczema, pale skin
ID, seizures
Musty odour to urine
Rx: Low Phe diet
Types of ciliopathies & features.
Joubert’s ( JBTS )
- AR
- Retinitis piigmentosa, ataxia, sleep apnoea/hyperpnea, polydactyly
- Absent corpus callosum
Dent’s- CLCN5 (1), ORCL1 (2)
- X-linked,
- Proximal RTA & stones
- Hypophosphatemic ricketts
Bardet-Biedl (BBS)
- Pleotropic
- Rod-cone blindness, polydactyly, obesity,LD
Meckel Gruber (MKS1/2)
- Encephalocoele, dysplastic kidneys, polydactyly
Senior Loken (NPHP)/Nephronopthisis
- SL: Juvelile NP/ progressive eye disease
- NP: polyuria/polydipsia, ESRF, CM cysts
McKusick Kaufman (MKS1)
- AD
- Hydrometrocolpos, hypospadias, ureteric atresia
Ellis-Van Creveld (EVC)
- Polydactyly, dwarfism, CHD/ASD, natal teeth, cleft
Leber congenital amaurosis
- Vision loss
PCD/Kartageners
PCKD
Usher syndrome=
hearing loss, ataxia and retinitis pigmentosa
Lowe Syndrome- Sx/gene
Oculocerebrorenal syndrome
OCRL1 gene- X linked
Bilateral cataracts from birth
Proteinuria/stones
Behavioral change/hypotonia
Kearns Sayre Syndrome (what syndrome can precede?)
Mitochondrial myopathy with proximal weakness
Retinal degeneration
Conduction block
Ataxia
Ragged red fibres on Bx
Preceded by Pearson’s Syndrome: sideroblastic anaemia, pancreatic insufficiency & LBW
Sx Lambert Eaton Syndrome
Genetic conditions associated with coloboma?
*Aicardi syndrome
*Basal cell nevus (carcinoma) syndrome
*Cat-eye syndrome
*CHARGE
*Kabuki syndrome
*Linear sebaceous nevus syndrome
*Meckel-Gruber syndrome
*Rubinstein Taybi syndrome
*Trisomy13,18
*WalkerWarburg syndrome
Examples of conditions due to haploinsufficiency?
Haploinsufficiency: reduction of 50% of gene function results in an abnormal phenotype
Williams syndrome
CHARGE syndrome
Cleidocranial dysostosis
EDS
Marfan syndrome
Holt-Oram
Which conditions display the dominant-negative effect?
Definition = altered gene product that acts antagonistically to the wild type
Cancer – p53, ATM
Marfan syndrome
Russel Silver, BWS, Prader Wili & Angelman genetics
Chromasome 7/11p
Russel-Silver syndrome
- Maternal UDP 7 (7%)
- Imprinting defects on 11p (30%)
- Structural chromosomal aberrations (1%)
Beckwith WiedeMANN
- Imprinting defects on 11p (60%)
- Paternal UDP 11p (20%)
- Gene mutation (CDKN1C) (10%)
- Paternal duplication, inversion, translocation (1-2%)
Chromosome 15
AngelMAN
- Microdeletion (70%)
- Paternal UDP 15 (1-3%)
- UBE3A mutation (5-10%)
- Imprinting defect (3-5%)
Prada-Willi syndrome
- Microdeletion (70%)
- Maternal UDP 15 (25%)
- Imprinting defect (3%)
Russel Silver, BWS, Prader Wili & Angelman symptoms
Russel Silver
- Hemihypertrophy (small)
- Triangular face
- Decreased bone age
BWS
- Overgrowth
- Macroglossia
- Ear pits/tags
- Abdominal wall defects, risk embryonal tumors
- Hypoglycemia, obesity
Prader Wili
- Hypotonia/hyperglycemia
- Feeding difficulties
- ID
- Hypogonadism
Angelman
- Severe ID
- Inappropriate laughter
- Ataxia/seizures
MRI findings in Jouberts (cerebello-oculo-renal syndrome)?
Molar tooth sign (cerebellar vermis hypoplasia)
- 25% will have nephronophthisis or renal dysplasia
Define cascade testing in genetics?
- Cascade testing involves determining whether or not it is present in other family members beyond the parents.
Define segregation in genetics?
- Segregation is the process of determining whether a variant of interest found in a patient is present in parents.
