Block 1 Genetics Flashcards
Lifetime frequency of genetic disorders, rate of chromosomal abnormality -> spont abortion, newborns with gross chr abn, % from 1-25 with genetic comp disease
Life: 670/1000
Spont: 50%
Gross: 1%
Gen comp: 5%
Variable penetrance
Gene doesn’t penetrate all the way to phenotype
Anticipation
Gets worse with each generation; ex: FRAX, HD, myotonic dystrophy
Polymorphisms
Gene with at least 2 alleles tin at least 1% population, each with modest effect and low penetrance
Down Syndrome
1/700
Flat, epicanthal folds, Simian crease, nuchal skin, congenital heart VSD, leukemia, TB, pneumonia, AD
Robertsonian translocation
14q21q chromosome, can cause trisomy 21
Down syndrome and AD?
Critical gene region for AD on chromosome 21
Genes important in Down Syndrome
DYRK1A (heart, brain), P Tau protein
DSCR1 - synapse malfunction
Both = regulate TF NFATc -> CNS development
Down Syndrome & green tea
EGCG in green tea –| DYRK1A
Down Syndrome & tumors
DSCR1 -> protein –| VEGF
Upregulated DYRK1A + DSCR1 –| tumor angiogenesis
Marfan syndrome
AD; increased height, ectopia lentis, double-jointed, arachnodactyly, aorta ruptures ~30
Due to fibrillin-1 defect (elastin scaffolding)
Ehlers-Danlos syndrome
Collagen problem, commonly AD, wound repair problems
Type 4: colon blows at 16 - type 3 procollagen *vascular
Type 6: most common, cornea slides off - lysyl hydroxylase
Type 10: copper
Familial hypercholesterolemia
AD; LDL-R defect -> atherosclerosis, elbow & eyelid lipoma; 1/500 heterozygotes in population
Cystic fibrosis
AR; 3-base deletion df508 –> CFTR; cystic and fibrotic pancreas -> malnutrition, steatorrhea, lung infections; meconium plug at birth, male infertility
Tay-Sachs disease
AR; HEX-A (chr 15), GM2 gangliosides; ~1 year, mental, physical degeneration -> 2,3 YOA. Cherry red spot on macula
Sandhoff disease
AR; HEX-B (chr 5) gene codes for protein essential to HEX-A,B, death by age 3
Niemann-Pick disease
AR; NPC1,2, SMPD1 genes -> sphingomyelinase
Neurons, liver, spleen, bone marrow, others; “onion-skin” myelin bodies on EM, cherry red spot
Gaucher’s disease
AR; beta-glucosidase (lysosomal gluco-cerebrosidase) housekeeper -> glucocerebroside
1: adult, mild, Ashk. Jews
2: infant, severe, anybody (hepatosplenomegaly)
3: juvenile, moderate, specific families (pathologic fracture, hepatosplenomegaly)
Hunter/Hurler syndromes
Mucopolysaccharidoses; “gargoyle kids”; X-linked; alpha-L-iduronidase; clouded cornea, stiff joints, hepatosplenomegaly, MR, atherosclerosis
Pompe’s disease
AR; lysosomal glucosidase (acid maltase), type 2 glycogen storage disorder, myopathic; severe form is fatal early with mm weakness, hypotonia, cardio/hepatomegaly; mild form resembles limb-girdle dystrophy (heart, mm, NS, leukos, liver, kidney)
Von Gierke disease
Type 1 GSD; glucose-6-Pase
Cori disease
Type 3 GSD; debranching enzyme
Andersen disease
Type 4 GSD; branching enzyme
McArdle disease
Type 5 GSD; muscle glycogen phosphorylase
Hers disease
Type 6 GSD; glycogen phosphorylase
Tarui disease
Type 7 GSD; muscle PFK
Galactosemia
Galactose-1-phosphate uridyl transferase deficiency -> cataracts; can’t break down galactose (in milk), jaundice, cirrhosis, ascites
Alkaptonuria (ochronosis)
Homogentisic acid oxidase -> Phe, Tyr can’t degrade fully -> black urine; rheumatism, black spots in weird places (whites of eyes, nose, inside ears)
Neurofibromatosis types 1 and 2
Cafe au lait spots >3 cm, neurofibromas throughout life
1: Von Recklinghausen’s disease
2: schwannomas, meningiomas, no Lisch nodules (iris)
Von Recklinghausen’s disease
Neurofibromatosis type 1; 17q11.2 NF1 gene from neural crest -> many sarcomas, early metastases; MR, rare cancers, Lisch nodules (iris), skeletal erosions
Edwards syndrome
Sporadic trisomy 18; prominent occiput, MR, low ears, micrognathia, short neck, cong heart, renal malform, rocker-bottom feet; die by 18 months
Patau syndrome
Sporadic trisomy 13; microcephaly, holoprosencephaly, MR, microphthalmia/cyclops, cleft lip/palate or elephant nose, cardiac, umb hernia or gastroschisis, rocker-bottom feet, polydactyly
DiGeorge syndrome
Del 22q11.2 *T cell defects!
No branchial arches 2-4, hearts, faces, thymus
Klinefelter’s syndrome
XXY -> sweet, slightly MR, slight breasts, small testes, not much hair, often infertile
XYY syndrome
Taller, worse acne, no MR, may be more delinquent/impulsive
Turner syndrome
XO; short, slight MR, streak ovary, webbed neck, valgus elbows, coarctation of aorta; often mosaic
XXX, XXXX, etc.
Increased # = increased MR
Hermaphroditism
True = very rare
Male pseudo is XY with feminized genitalia (deficient androgenization)
Female pseudo is XX with masculinized genitalia (excessive androgenization, virilizing adrenal hyperplasia *salt wasting)
Testicular feminization
XY with no androgen receptors but normal testosterone levels; beautiful, long-legged, symmetrical, no menstruation because no uterus or cervix, blind vagina
Fragile X syndrome
Triplet repeats of CGG, Xq27; oogenesis, MR, long face, large mandible, large everted ears, macroorchidism, anticipation
Huntington’s Disease
CAG triplet repeats, AD
Friedrich’s Ataxia
GAA triplet repeats on chr 9 FRDA gene for Frataxin; gait then all limb ataxia, puberty onset, in wheelchair by 25, death by cardiomyopathy
Prader-Willi syndrome
Deletion at paternal 15q12 or maternal disomy 15; short, fat, male, MR
Angelman syndrome
Deletion at maternal 15q12 or paternal disomy 15; severe MR, very happy
