Genetics Flashcards
Fragile X Syndrome
- Most common inherited and 2nd most common congenital cause of intellectual disability
- x-linked d/o c/b loss of function mutation in FMR1
- trinucleotide repeat = (CGG)n
- females with 1 abnormal X have milder and variable sx
Features:
- long, narrow face
- prominent forehead and chin
- large testes
- hyperlaxity of hand joints
- developmental delay (speech and motor) in infancy
- neuropsych sx in childhood (e.g. anxiety, ADHD, autism spectrum)
Number 1 cause of congenital intellectual disability
Down Syndrome
- epicanthal folds
- upslanting palpebral features
- low-set small ears
- flat facial profile
- sandle-toe deformity
- single palmar crease
- Brushfield spots (in iris)
- duodenal atresia
- congenital heart dz (ASD)
- inc risk of ALL and Alzheimer’s dz (>35 yo)
Quad screen: dec alpha-fetoprotein, dec estriol, inc inhibin A, inc beta-hCG
Ehlers-Danlos syndrome
connective tissue d/o
most common mutation = type V collagen production
sx = skin hyperelasticity and fragility, joint laxity
Klinefelter syndrome
47, XXY
mild ID tall stature gynecomastia small testes (often undescended) infertility
Marfan syndrome
AD, fibrillin-1 gene mutation–> connective tissue d/o
- tall stature
- arachnodactyly (long and thin fingers)
- ectopia lentis (lens displacement)
- dilation of proximal aorta –> dissectic aortic aneurysms
- inc arm:height ratio
- dec upper:lower body segment ratio
- pectus excavatum
Prader Willi syndrome
paternal deletion of part of chromosome 15
infancy –> hypotonia and associated gross motor delays, hyperphagia and associated obesity
ID and behavioral problems common (e.g. autistic behaviors, OCD features)
Wilson disease
dx = dec serum ceruloplasmin, inc hepatic copper
cirrhosis, CNS involvement, Kayser-Fleischer rings
Hemochromatosis
dx = high serum ferritin levels
cirrhosis, pancreatic fibrosis, subsequent DM, CM (cardiomyopathy), secondary hypogonadism
Fabry Disease
inherited deficiency of alpha-galactosidase A
globoside ceramide trihexoside accumulates in tissues
sx = hypohidrosis, acroparesthesia (episodic burning neuropathic pain in extremities) and angiokeratomas (punctate dark non-blanching macules and papules between umbilicus and knees)
tx = enzyme replacement therapy to avoid renal failure and death
alpha 1 antitrypsin deficiency
panacinar emphysema and liver cirrhosis
alpha 1 antitrypsin = serine protease inhibitor that normally inactivates elastase and trypsin
Lesch-Nyhan
sx = spasticity, choreoathetoid movement, self-mutilation
c/b HGPRT absence (which converts hypoxanthine to IMP and guanine to GMP) –> defective purine salvage pathway –> excess uric acid production and de novo purine synthesis
“He’s Got Purine Recovery Trouble”
X-linked recessive
Niemann-Pick disease
spasticity
Adenosine deaminase deficiency
excess ATP and dATP –> feedback inhibition of ribonucleotide reductase –> prevents DNA synthesis –> decreased lymphocyte count –> SCID
Achondroplasia
AD
cell-signaling defect in fibroblast growth factor (FGF) receptor 3 –> dwarfism, short limbs, larger head, normal trunk, i.e. Tyrion Lannister
assoc. with advanced paternal age
ADPKD
AD
- always b/l
- massive kidneys from cysts
- sx = flank pain, hematuria, HTN, progressive RF
85% 2/2 PKD1 mutation (chromosome 16)
assoc. conditions:
- polycystic liver dz
- berry aneurysms
- mitral valve prolapse
*infantile form = recessive
Familial adenomatous polyposis
AD
colon covered with polyps after puberty –> colon cancer unless resected
mx on chromosome 5 in APC gene
Familial hypercholesterolemia (hyperlipdemia type IIA)
AD
Elevated LDL due to defective or absent LDL receptor
heterozygotes (more common) = LDL ~300
homozygotes (rare) = LDL ~700+
severe atherosclerosis at young age, tendon xanthomas (esp Achilles), MI before age 20
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
AD
inherited d/o of blood vessels
findings: telangiectasiasm recurrent epistaxis, skin discolrations, AVMs
Hereditary spherocytosis
AD
spectrin and ankyrin defect –> spherocytes
findings: hemolytic anemia, inc MCHC
cure = splenectomy
Huntington’s disease
AD
findings: depression, progressive dementia, choreiform movements, caudate atrophy, and dec levels of GABA and ACh in the brain
sx onset = 20-50 yo
trinucleotide repeat (CAG)n on chromosome 4
“hunting 4 food”
MEN 1
AD
pituitary, parathyroid, pancreas
MEN 2A
AD
pheochromocytoma, parathyroid hyperplasia, medullary thyroid cancer
ret gene
MEN 2B
AD
pheochromocytoma, medullary thyroid cancer, marfanoid habitus, mucosal neuromas
ret gene
Neurofibromatosis type 1 (von Recklinghausen’s disease)
AD
cafe au lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas), scoliosis, optic pathway gliomas
long arm of chromosome 17
NFT2
b/l acoustic schwannomas, juvenile cataracts
NF2 gene on chromosome 22
Tuberous sclerosis
AD
facial lesions (adenoma sebaceum, hypopigmented “ash leaf spots”, cortical and retinal hamartomas, sz, ID, renal cysts, renal angiomyolipomas, cardiac rhabdomyomas, inc incidence of astrocytomas
incomplete pentrance
4 systems affected = CNS, skin, cardiac, renal
von Hippel-Lindau disease
AD
hemangioblastomas or retina/cerebellum/medulla
multiple b/l RCC and other tumors
deletion of VHL gene (tumor suppressor) on chrom 3p –> constitutive expression of hypoxia inducible factor HIF-1 (TF) and activation of angiogenic GFs and EPO –> inc vascular endothelial growth
pheochromocytomas can occur in conjunction
Cystic Fibrosis
AR defect in CFTR on chromosome 7 (commonly del of Phe 508) –> misfolding and degradation of channel before reaching cell surface
sx= chronic bronchitis, recurrent PNA (s. aureus, pseudomonas), bronchiectasis, pancreatic insufficiency (steatorrhea, malabsorption), nasal polyps, meconium ileus, infertility in males due to absent vas deferens b/l, fat-soluble vit deficiencies (ADEK), failure to thrive
dx = Cl sweat test showing Cl elevation tx = N-acetylcysteine to loosen mucus plugs (cleaves S-S bonds in mucus glycoproteins)
CFTR
- Cl secretion in lungs and GI tract
- Cl reabsorption from sweat
most commonly a deletion at position 508 of codon coding for phenylalanine
can also be c/b frameshift mx
X-linked recessive d/o
“Be Wise, Fool’s GOLD Heeds Silly HOpe”
Bruton's agammaglobulinemia Wiskott-Aldrich syndrome Fabry's disease G6PD deficiency Ocular albinism Lesch-Nyhan syndrome Duchenne's (and Becker's) muscular dystrophy Hunter's Syndrome Hemophilia A and B, Ornithine transcarbamoylase deficiency
Duchenne’s muscular dystrophy
x-linked frameshift mutation –> del of dystrophin gene (fxn = anchor muscle fibers) –> accelerated muscle breakdown
sx = weakness in pelvic girdle muscles and progresses superiorly, calf pseudohypertrophy, cardiac myopathy, Gower’s maneuver
dx = inc CPK and muscle biopsy
onset before 5 yo k
Becker’s muscular dystrophy
mx in dystrophin gene but less severe than Duchenne
onset = adolescence or early adulthood
Trinucleotide repeat expansion disease
“Tried HUNTING for MY FRIED eggs(X)”
“X-Girlfriend’s First Aid Helped Ace My Test”
Fragile X - CgG –> c guy’s giant junk
Friedreich’s ataxia - CaA
Huntington’s disease - CaG –> hunting to cage
Myotonic dystrophy - CtG –> can’t try to game too weak
Edward’s syndrome
trisomy 18
severe ID, rocker-bottom feet, micrognathia, low-set ears, clenched hands, prominent occiput, congenital heart disease
death by 1 yo
quad screen: dec alpha-fetoprotein, dec beta-hCG, dec estriol, nl inhibin A
Patau’s syndrome
trisomy 13
severe ID, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease
death by 1 year
1st trimester screen: dec free beta-hCG, dec PAPP-A, inc nuchal translucency
Cri-du-chat syndrome
Congenital microdeletion of short arm of chromosome 5 (46, XX or XY, 5p-)
microcephaly, moderate to severe ID, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD)
Williams syndrome
Congenital microdeletion of long arm of chromosome 7 including elastin gene
distinct elfin facies, ID, hypercalcemia (inc sensitivity to vit D), well-developed verbal skills, extreme friendliness with strangers, CV problems
22q11 deletion syndromes
CATCH-22 thanks to microdeletions and aberrant development of 3rd and 4th branchial pouches
Cleft palate Abnormal facies Thymic aplasia --> TC deficiency Cardiac defects Hypocalcemia 2/2 parathyroid aplasia
DiGeorge = thymic, parathyroid, and cardiac defects
Velocardiofacial syndrome - palate, facial, and cardiac defects
Robertsonian translocation
nonreciprocal
commonly involves pairs 13, 14, 15, 21, 22
long arms of 2 acrocentric chrom (i.e. centromeres near ends) fuse at centromere and 2 short arms lost
Bruton’s X-linked agammaglobulinemia
p/w recurrent sinopulmonary infections, Giardia lamblia gastroenteritis, failure to thrive, low of all Ig levels, inc risk of pyogenic (encapsulated) bacT infection
mx in Bruton tyrosine kinase –> failure of BM pre-B cells (CD19+, CD20+) to develop into mature BCs (CD19+, CD20+ CD21+).
