Genetics Flashcards
Pleiotropy meaning
Genes that gave more than one discernible effect on the phenotype for example CFTR, Marfans, osteogenesis imperfecta
Alpert syndrome gene and inheritance pattern
FGFR2 (fibroblast growth factor receptor 2) AD
Two examples of micro deletions
22q11 and Williams
X linked dominant disorder
Incontinetia pigmenti
Other x linked recessive fragile x on FMR1 gene, haemophilia, duchenne and Becker
Autosomal dominant - name five
Noonan Charge Alagille NF 1 Marfan Ehlers danlos Stickler Achondroplasia Myotonic dystrophy TS Cornelia de Lange
Limit of microarray
Misses balanced translocation
CHARGE
Coloboma Heart Atresia of choanae Retardation growth or mentation Genital abnormalities Ear abnormalities
CHD7 gene
Ddx kabuki and retinoic embropathy
Heteroplasmy
The presence of both normal and mutation carrying mitochondrial DNA in a cell
Aneuploidy caused by
Failure of homologous chromosomes to separate in anaphase I, failure of sister chromatids to separate at meiosis II
Alagille inheritance
AD but 70% de novo (JAG1 gene chr 20p12)
<1% NOTCH2
Ataxia telangiectasia clinically
Ataxia
Telangiectasia
Dev delay
Immunodeficiency
Wiskott Aldrich clinically
Symptoms:
Petechiae (microthrombocytopenia)
Eczema
Immunodeficiency - Chronic draining ears (sinopulm infections)
Ix:
low immunoglobulin M (IgM) and immunoglobulin G (IgG) levels, normal-to-high immunoglobulin A (IgA) and immunoglobulin E (IgE) levels
No response to vaccine
Gene test WAS gene making WAS protein or WASP
XL (male 1-10 per million males)
Badder-biedl
AR variable Short and fat Retinitis pigmentosa Polydactyly Hypogonadism ID
Beckwith-wiedemann
Disorder of imprinted gene 11p15 Overexpression IGF2 Overgrowth, organomegally, omphalocoele Hypoglycaemia Ear crease and pits Tumours
Cornelia de lange
IUgR Mono brow Severe ID Limb abnormalities Cardiac Gut malrotation Self harm behaviour
Most common thing associated 15% downs
Coeliac
Can have transient myeloprolif at birth (normalises by 2m)
Noonan syndrome clinically
PS (ASD, HOCM)
Short
Web neck and triangular face, Epicanthus with slanted eyes, ptosis, low set ear, mild low IQ
Small testes and delayed puberty
Stickler and Marshall due to..
Type 2 collages defect
Smith lemil opitz due to
Defect in cholesterol metabolism elevated 7-dehydrocholesterol AR DHCR7 gene Microcephalic, ambiguous genitalia males Micrognathia Anteverted nostrils Adrenal insuf Syndactyly Severe ID Tx: cholesterol
VACTERAL
Vertebral Anal atresia Cardiac TOF EA Renal Limb
Velocardiofacial (22q11)
22q11 deletion (TBX1 and COMT)
1/4000
Sporadic (7% inherited AD)
Cleft palate with bifid uvula
VSD, conotruncal, commonly interrupted aortic arch B
Long face hypotonic with bulbous tip broad nose
Williams
AD, 20 gene deletion on chr 7
FiSH (microdeletion)
Prominent lips, fat around eyes, big ears, blue eyes, stellate pattern on iris, elfin facies hypercalcaemia in infancy (resolves)
cocktail personality
Short stature and FTT
Cardiac abnormalities
– Supravalvar aortic stenosis 50%
–Peripheral pulmonary stenosis 27%
Intellectual disability ~100%
anxiety
Zellweger
Peroxisomal disorder Hypotonia Absent reflexes Hearing and visual loss Seizures High forehead, large fontanell Hepatomegally Die infancy no Rx
Aneuploidy
Wrong no. Chromosomes
Haplotype
Group of nearby or closely linked genes or alleles on chromosome that are inherited together
DNA helixase job
Denaturation , separation of strands
Southern vs northern blot
Southern DNA and northern RNA
Most common congenital condition
Bilateral hearing impairment
Cause of symptoms in female with x linked disorder
Lyonisation
Sickle cell and thalassaemia inheritance
AR
First cousins share how much genetic material
1/8th
Risk sibling with autism
20%
Allergy if one parent or two first degree relatives
50%
75%
Diabetes if one first degree
5%
Sibling with CHD
One first degree 2.5% or two is 20-30%
Three AR conditions
Smith lemli opitz
Ataxia telangiectasia
Mucopolysaccharidoses
Costello syndrome
New AD FTT Hand wrist position Cardiac abn 10-15% risk cancer
Cardiofaciocutaneous syndrome
New AD HCMO, PS Tall forehead, sparse fine curly hair FTT Sz DD
Fragile x related
Fragile x tremor ataxia syndrome (adults) and premature ovarian insufficiency
PWS test
DNA methylation studies
Trinucleotide repeat d/o
Fragile x (CGG) Myotonic dystrophy (CTG) Friederich ataxia (GAA)
AD inheritance
Parent of affected person usually affected
Either sex and transmitted by either
50% chance offspring affected
AR
Affected person usually carrier parents not affected
Affects either sex
25% risk affected child and 2/3rds siblings are carriers
Allergic heterogeneity means
Many different types of mutations in a gene can result in same disorder
Locus heterogeneity
Mutations in many different genes can result in same disorder (such as long QT)
Example of incomplete penetrate and variable expressively
Incomplete penetrate (familial retinoblastoma) Variable expression (Marfans)
Heteroplasmy means
Presence of both normal and mutation carrying mitochondrial DNA in a cell
How much of our genome codes protein
2%
Missense and nonsense mutations
Missense alter coding sequence
Nonsense insert truncating codon
Allelic heterogeneity
Causation of a disease phenotype from a variety of different genotype
Germ line mosaicism example
Osteogenesis imperfecta
Inactivation of one X chromosome happens when
About 2 weeks after fertilisation (starting at inactivation centre then spreading along chromosome)
Example of mitochondrial disorders
MELAS (mitochondrial encephalopathy stroke like episodes and lactic acidosis)
Leigh
Pearson syndrome
Balanced robertsonian translocation in downs recurrence
Father (1-2%)
Mother (10%-15%)
Trisomy 13 patau syndrome
Cleft
Posterior polydactyly limbs
Holoprosencephaly
Recurrence risk T13 and T18
1%
Incontinentia pigmenti signs
Abortions Dentition Sz Hair Dev delay
Ichthyosis skin
Fish scale
Sturge Weber
Leptomeningeal angiomyolipomas Urgent ophthalmology (glaucoma)
Kasabach-Merritt
Kaposiform haemangioendotheliomas or tufted angiomas Thrombocytopenia and coagulopathy Fibrin consumption Anaemia Up to 50% die without Tx (tx sirolimus) (Not infantile haemangioma)
Waardenburg
Hearing
Different coloured eyes
White forelock
Broad nose
PHACE syndrome
Post fossa malformation Haemangioma Arterial anomalies Cv anomaly Eye anomaly
Number of ribs in trisomy 21
11
Williams syndrome 90% have which deletion
7q11.23
CHD in Noonan
Pulm stenosis 50%
Hypertrophic cardiomyopathy 20%
Cyanosed trisomy 21 has
TOF
D TGA related to genetic syndrome
Rarely
Situs inversus
Assoc dextrocadia and L-TGA (3-5%)
20% have kartageners
Left atrial isomerism and right ?spleen
Polysplenia (multiple small non functioning) in left and asplenia in right
Potters sequence
From oligohydramnios - pulm hypoplasia, cranial and facial abnormalities and clubbed feet
ARPKD can cause it (NO cysts in kidney)
Tendon xanthomas indicate
Familial hypercholesterolaemia or familial defective apoprotein B100
High what blood test in ataxia telegectasia?
Alpha feto protein
Leukocyte adhesion def type 1 presentation
Delayed umbilical cord separation and sepsis
Achondroplasia is a conical diagnosis but gene test is for..
99% of individuals with
achondroplasia have an amino acid substitution at position 380 (Gly380Arg) in the
FGFR3 gen
Bilateral ear pits could be from what syndrome
branchio-oto-renal
(BOR) syndrome. This autosomal dominant disorder caused by mutations in EYA1 is
associated with preauricular pits (70%-80%), branchial cysts or fistulas (30%-60%), and
structural renal anomalies (12%-20%). Therefore, renal ultrasonography is recommended
in light of the other 2 clinical findings. In addition to these features, individuals with
BOR syndrome may have other external ear malformations, and at least 75% have some degree of hearing loss
Achondroplasia inheritance and intelligence
Normal intelligence
Often sporadic and AD
Infant ashkani Jewish normal at birth then progressive hypotonia, inattentiveness, an exaggerated startle response, evidence of visual dysfunction, and cherry-red spots on retinal examination has?
Cherry rest spots also seen in
Tay-sachs
cherry-red spots are seen in many lipid
storage disorders, including GM1 gangliosidosis, Sandhoff disease, some of the mucopolysaccharidoses, Niemann-Pick disease, and mucolipidoses
Allelic heterogeneity –
Locus heterogeneity –
Allelic heterogeneity – Many different types of mutations in a gene can result in the same
disorder
e.g most disorders; exceptions: Huntington disease
• Locus heterogeneity – mutations in many different genes can result in the same disorder
e.g long QT syndrome (at least 7 different genes)
Variable expression but complete penetrative in what condition
22q11
Angelmans syndrome
AS: hypertonic, profound mental retardation, seizures, frequent smiling and laughing, growth retardatio, widely spaced teeth
Turners newborn
Web neck, puffy hands and feet and cardiac
Dental pits and confetti skin lesions seen in? (Minor criteria)
TS
Ungal fibromas, hypomelanotic lesions, facial adenomas age in TS
Hypo lesions at birth
Facial ‘acne’ 3-15y
Ungal fibromas after puberty
SEGA seen in what and how to manage
SEGA are growths into ventricles
Slow
Not responsive to chemo or radio (resect and manage hydrocephalus)
MTOR inhibitors
Cafe au Lai spots in which syndromes
NF 1 and 2
McCune Albright (jagged edge rarely cross midline)
Legius syndrome
LEOPARD syndrome
Watson, bloom, Russell-Silver
Short forth metacarpal due to?
Turners
FAS
Pseudohypoparathyroidism
Gorlin
Homocysteinuria
Sickle cell infarct
Leri‐Weill dyschondrosteosis
Haploinsufficiency of the SHOX gene is also responsible for short stature in Turner syndrome.
Turner syndrome. sHOX gene has dose effect
Mother affected and child has vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. Also involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, and hormonal imbalances.
MELAS
What syndrome is characterized by a progressive loss of vision and hearing, a form of heart disease that enlarges and weakens the heart muscle (dilated cardiomyopathy), obesity, type 2 diabetes mellitus (the most common form of diabetes), and short stature.
Alström syndrome
Present with retinitis pigmentosa and deafness
Usher syndrome
What syndrome?
Affected individuals can exhibit growth retardation, short stature, premature graying of hair, hair loss, wrinkling, prematurely aged faces, beaked noses, skin atrophy (wasting away) with scleroderma-like lesions, loss of fat tissues, abnormal fat deposition leading to thin legs and arms, and severe ulcerations around the Achilles tendon and malleoli. Other signs include change in voice, making it weak, hoarse, or high-pitched; atrophy of gonads, leading to reduced fertility; bilateral cataracts (clouding of lens); premature arteriosclerosis (thickening and loss of elasticity of arteries); calcinosis (calcium deposits in blood vessels); atherosclerosis (blockage of blood vessels); type 2 diabetes; loss of bone mass; telangiectasia; and malignancies. In fact, the prevalence of rare cancers, such as meningiomas, are increased.
Werner syndrome
Present with short stature, a skin rash that develops after exposure to the sun, and a greatly increased risk of cancer.
Bloom syndrome
Screen for wilms in
WT1 deletions (11p13) = WAGR syndrome • Wilms 50%, Aniridia (no iris) 100% (PAX6 del), GU, Retardation • WT1 missense mutation = Denys‐Drash syndrome • Nephropathy and intersex • FWT1 (17q12‐q21)
Gene for rett
MECP2
Severe insulin resistance syndrome called
?
Presents with SGA, acanthosis nigracans, lipodystrophy, hairy ALL over and typical facial features
Donohue
Biliary obstruction with large liver differential cause
Choledochal cyst
Hearing loss and goitre syndrome
Pendred syndrome
Trichorrhexia invaginata (bamboo hair), severe eczema, FTT, recurrent infections causes by
Netherton syndrome
Impaired immunity, thrombocytopenia and eczema from what syndrome
Wiskott-Aldrich
Wilsons gene
ATP7B
Alpha 1 antitrypsin def gene
SERPINA1
Progressive familial intrahepatic cholestasis 1 gene
PFAC1 (FIC def) chr 18q12
Excessive physical growth is what syndrome
Sotos
Pakinsonian features and tremors
MRI findings giant panda (abnormal signal in globes pallidus, puts men, substanstia nigra)
Wilson’s disease
What does DNA and RNA polymerase do
Synthesise rna and DNA
Syndromes associated with histologicsl absence of meissners and auerbachs plexsus with high achetylcholinesterase
Downs, Joubert, smith-lemli-opitz, NF, Ondine’s curse
Gene mutations in hereditary pancreatitis (chronic in children often from genetic mutations)
SPiNk 1
CTFR
cTRC
Holoprosencephaly is associated with what cardiac abnormality
AOLCA
Marfanoid habitus differential
Marfans mASS Homocysteinuria (lens down and out instead of UP in marfans) Stickler Shprintzen goldberg
Glaucoma associated with (3)
Rubella
Lowe syndrome
Sturge Weber
Alopecia arrests associated with? What positive test
Atopy, autoimmune, Fhx
Positive pull test and nail changes
Differential to gum bleed (presents like vwd)
Bernard-soulier syndrome (defect in glycoproteins Ib the receptor for vwf)
Platelet transfusion is matched with
The ABO and rhesus (especially if negative)
I.e if patient A- use A- platelets
Irradiated preferred
Can be from single or pooled - no difference in reaction rate
G6PD inheritance
XL recessive
Subtle triangle face and small eyes and thumb/radial abnormality dysmorphisms of what
Fanconi
Beak nose and broad thumb in what
Rubinstein-taybi
What immune marker low in prem vs term
Immunoglobulins
What following observations regarding a rare disorder would provide the best evidence of
autosomal dominant inheritance?
Father and son affected
Mutation in DMd
Deletion of several exams in Dystrophin gene
Child with short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes. Additional features of the disorder can include eye abnormalities, heart and kidney defects, dental problems, and obesity.
Rubinstein-Taybi syndrome
CREBBP gene
Child with light skin, silvery hair, recurrent infections (immune deficiency) and easy bleeding
Also visual problems/clumsiness (peripheral neuropathies)
Chediak-Higashi syndrome
3 year old child under 10th centime growth (short), microcephalic, dangling thumbs, dislocated hips, rocker bottom feet, cafe au lait
Anaemia or aplastic anaemia
Fanconi anaemia
Short girl always consider
Karyotype for turners
Presents with imperforate anus, renal, polydactyly, syndactyly and hypothalamic hamartoma
Pallister hall
Gene associated with ARPKD salt and pepper appearance kidney on USS)
PKHD1
Presents with acidic stools containing sugar and defect in SGLT1 called
Glucose-galactose malabsorption
Present with short boy rickets with low phosphate and normal vitamin d level and high ALP
What genetic test to confirm diagnosis?
PHEX
X-linked hypophosphatemia (inability transporter to get to apical membrane to reabsorb phosphate in kidney)
LEOPARD syndrome
L – lentigines (multiple brown-black spots on the skin)
E – electrocardiographic (ECG) conduction defects
O – ocular hypertelorism
P – pulmonary stenosis
A – abnormalities of genitals
R – retarded growth resulting in short stature
D – deafness or hearing loss due to inner ear malfunction
CTRC gene associated with
Hereditary pancreatitis
Congenital nephrotic syndrome NPhS1 and 2 code for
Nephrin and podocin
What syndrome?
Red skin, bamboo hair, atopy
Nethertons syndrome
Persistent tachypnoea infant syndrome
Neuroendocrine cell hyperplasia of infancy
Which disease characterized by (nervous system involvement) hypotonia, peripheral neuropathy, ataxia, retinitis pigmentosa (vision), hearing
(Liver and kidneys)
AR perixsomal d/o Refsum disease (mild form of zellweger spectrum, zellweger severe form, adrenoleukodystrophy intermediate and refsum mild)
Blue eyes with stellate pattern iris in
Williams
Dural ectasia causes (3)
Marfans (major criteria and 60% have)
NF
Osteogenesis imperfecta
Mnemonic NOONANS
Neurodevelopmental problems, neuromuscular (hypotonia –
floppy strong, joint hyperextensibility), neurosurgical (Arnold-
Chiari type I).
Obstructive heart lesions: RVOT (pulmonary valve), LVOT
(HCM). Other: ASD, VSD, TOF, coarctation, branch pulmonary
artery stenosis.
Ocular abnormalities: strabismus, refractive errors, amblyopia,
nystagmus, hypertelorism, epicanthic folds, droopy eyelids,
vivid blue or blue green irises.
Neoplasia risk: JMML, myeloproliferative disorders, multiple
giant cell lesion syndrome (granulmoas and joint and bone
anomalies), hepatosplenomegaly (subclinical myelodysplasia).
Abnormal coagulation, abnormal lymphatics (lymphedema and
lymphangiectasia).
Neck webbing with low set and posteriorly rotated ears,
nipples low set, nephrological anomalies (duplex, renal
hypoplasia).
Sternal deformity (superior carinatum, inferior excavatum),
short stature, secondary sexual characteristics (delayed
puberty, cryptorchidism), skin findings (café au lait etc)
Williams hypercalcaemia mnemonic
William’s syndrome.
Intellectual impairment (IQ average 50-60). Impaired vision.
Low tone. Low pitched or hoarse voice, vocal cord paralysis.
Lax joints. Loquacious, over friendly, excessively empathetic.
Impaired feeding (difficulty with food textures, vomiting).
ADHD symptomatology. Anxiety.
Mitral valve prolapse.
Supravalvular aortic stenosis. Spine (scoliosis, kyphosis).
Sternum (excavatum).
HYpercalcemia, hyperclaciuria, hypertension.
Peripheral pulmonary artery stenosis. Puberty early (not
precocious).
Elastin arteriopathy (aortic insufficiency, stenosis of
mesenteric arteries). Endocrine (hypothyroidism, IDDM). Elfin
face.
Renal anomalies (nephrocalcinosis, pelvic kidney).
Chronic otitis media. Characteristic personality.
Audiological problems (high frequency sensorineural hearing
loss, hyperacusis).
Linear growth failure.
Cognitive (poor visuospatial construction).
Appearance (broad brow, bitemporal narrowness, medial
eyebrow flare, short palpebral fissures, epicanthic folds, blue
stellate iris, short nose, full nasal tip, full cheeks, malar
hypoplasia, long philtrum, full lips, wide mouth, small jaw,
prominent earlobes).
Eyes (hypotelorism, strabismus, amblyopia, refractive errors).
Maloclussion, microdentia, enamel hypoplasia, widely spaced
teeth, missing teeth.
Intestinal problems (constipation, diverticulosis, coeliac
disease).
Abdominal pain (reflux oesophagitis, cholelethiasis,
diverticulitis, ischaemic bowel disease).
Gene involved in zellweger spectrum
Approximately 68 percent of individuals with a Zellweger spectrum disorder have a mutation in the peroxisome biogenesis factor 1 (PEX1) gene located on the long arm of chromosome 7 (7q21-22).
Peroxisomes in cytoplasm required to metabolise VLCFA thus these increased
GP1B defect with giant platelets and bleeding is
Bernard-soulier syndrome
Syndromes associated with craniosynostosis
Crouzon, Apert, Carpenter, Chotzen, Pfeiffer
BWS risk wilms
5-10%
On penetrence is?
When genetically Have both alleles but not the phenotype
The polymerase chain reaction (PCR) requires the use of a DNA polymerase. The action of the DNA
polymerase is best described as:
A. allowing primers to affix to the single strands.
B. causing double-stranded DNA to become singled-stranded.
C. extending the primers once they are affixed to the single strands.
D. inducing fluorescence of DNA.
E. splitting the single strand and the extended primer.
C
Hypotrophic hypogonadism, anosmia, renal, facial =
Kallmans syndrome
Asymmetric face (one side very abnormal) called?
Goldenhar or occulo-auricle-vertebral syndrome
Self mutilation and lip biting in?
Lesch-nyhan
RB1 and RET genetic defects of..
Retinoblastoma and MEN
IPEX syndrome
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome
Infertile, bronchiectasis and dextrocardia
Kartagener syndrome (PCD)
Hair has pili tortilla and fractures along hair shaft? Diagnosis
Menkes
Kabuki syndrome gene
MLL2
Long QT and hearing impairment called
Jervell and Lange-Nielsen syndrome
Long QT 1-3 genetics
Long QT1: KCNQ1
Long QT2: KCNH2
Long QT3: SCN5A
Fanconi anaemia mnemonic
FANCONI
Fragile chromosomes/ fluid in brain Abnormal kidney Not tall Cafe Aui Lai Odd eyes and ears No children Increased cancer risk (AML) 10-30%
