Block 1 Genetics

Question 1

Lifetime frequency of genetic disorders, rate of chromosomal abnormality -> spont abortion, newborns with gross chr abn, % from 1-25 with genetic comp disease

Answer 1

Life: 670/1000
Spont: 50%
Gross: 1%
Gen comp: 5%

Question 2

Variable penetrance

Answer 2

Gene doesn’t penetrate all the way to phenotype

Question 3

Anticipation

Answer 3

Gets worse with each generation; ex: FRAX, HD, myotonic dystrophy

Question 4

Polymorphisms

Answer 4

Gene with at least 2 alleles tin at least 1% population, each with modest effect and low penetrance

Question 5

Down Syndrome

Answer 5

1/700

Flat, epicanthal folds, Simian crease, nuchal skin, congenital heart VSD, leukemia, TB, pneumonia, AD

Question 6

Robertsonian translocation

Answer 6

14q21q chromosome, can cause trisomy 21

Question 7

Down syndrome and AD?

Answer 7

Critical gene region for AD on chromosome 21

Question 8

Genes important in Down Syndrome

Answer 8

DYRK1A (heart, brain), P Tau protein
DSCR1 - synapse malfunction
Both = regulate TF NFATc -> CNS development

Question 9

Down Syndrome & green tea

Answer 9

EGCG in green tea –| DYRK1A

Question 10

Down Syndrome & tumors

Answer 10

DSCR1 -> protein –| VEGF

Upregulated DYRK1A + DSCR1 –| tumor angiogenesis

Question 11

Marfan syndrome

Answer 11

AD; increased height, ectopia lentis, double-jointed, arachnodactyly, aorta ruptures ~30
Due to fibrillin-1 defect (elastin scaffolding)

Question 12

Ehlers-Danlos syndrome

Answer 12

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

Question 13

Familial hypercholesterolemia

Answer 13

AD; LDL-R defect -> atherosclerosis, elbow & eyelid lipoma; 1/500 heterozygotes in population

Question 14

Cystic fibrosis

Answer 14

AR; 3-base deletion df508 –> CFTR; cystic and fibrotic pancreas -> malnutrition, steatorrhea, lung infections; meconium plug at birth, male infertility

Question 15

Tay-Sachs disease

Answer 15

AR; HEX-A (chr 15), GM2 gangliosides; ~1 year, mental, physical degeneration -> 2,3 YOA. Cherry red spot on macula

Question 16

Sandhoff disease

Answer 16

AR; HEX-B (chr 5) gene codes for protein essential to HEX-A,B, death by age 3

Question 17

Niemann-Pick disease

Answer 17

AR; NPC1,2, SMPD1 genes -> sphingomyelinase

Neurons, liver, spleen, bone marrow, others; “onion-skin” myelin bodies on EM, cherry red spot

Question 18

Gaucher’s disease

Answer 18

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)

Question 19

Hunter/Hurler syndromes

Answer 19

Mucopolysaccharidoses; “gargoyle kids”; X-linked; alpha-L-iduronidase; clouded cornea, stiff joints, hepatosplenomegaly, MR, atherosclerosis

Question 20

Pompe’s disease

Answer 20

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)

Question 21

Von Gierke disease

Answer 21

Type 1 GSD; glucose-6-Pase

Question 22

Cori disease

Answer 22

Type 3 GSD; debranching enzyme

Question 23

Andersen disease

Answer 23

Type 4 GSD; branching enzyme

Question 24

McArdle disease

Answer 24

Type 5 GSD; muscle glycogen phosphorylase

Question 25

Hers disease

Answer 25

Type 6 GSD; glycogen phosphorylase

Question 26

Tarui disease

Answer 26

Type 7 GSD; muscle PFK

Question 27

Galactosemia

Answer 27

Galactose-1-phosphate uridyl transferase deficiency -> cataracts; can't break down galactose (in milk), jaundice, cirrhosis, ascites

Question 28

Alkaptonuria (ochronosis)

Answer 28

Homogentisic acid oxidase -> Phe, Tyr can't degrade fully -> black urine; rheumatism, black spots in weird places (whites of eyes, nose, inside ears)

Question 29

Neurofibromatosis types 1 and 2

Answer 29

Cafe au lait spots >3 cm, neurofibromas throughout life 1: Von Recklinghausen's disease 2: schwannomas, meningiomas, no Lisch nodules (iris)

Question 30

Von Recklinghausen's disease

Answer 30

Neurofibromatosis type 1; 17q11.2 NF1 gene from neural crest -> many sarcomas, early metastases; MR, rare cancers, Lisch nodules (iris), skeletal erosions

Question 31

Edwards syndrome

Answer 31

Sporadic trisomy 18; prominent occiput, MR, low ears, micrognathia, short neck, cong heart, renal malform, rocker-bottom feet; die by 18 months

Question 32

Patau syndrome

Answer 32

Sporadic trisomy 13; microcephaly, holoprosencephaly, MR, microphthalmia/cyclops, cleft lip/palate or elephant nose, cardiac, umb hernia or gastroschisis, rocker-bottom feet, polydactyly

Question 33

DiGeorge syndrome

Answer 33

Del 22q11.2 *T cell defects! | No branchial arches 2-4, hearts, faces, thymus

Question 34

Klinefelter's syndrome

Answer 34

XXY -> sweet, slightly MR, slight breasts, small testes, not much hair, often infertile

Question 35

XYY syndrome

Answer 35

Taller, worse acne, no MR, may be more delinquent/impulsive

Question 36

Turner syndrome

Answer 36

XO; short, slight MR, streak ovary, webbed neck, valgus elbows, coarctation of aorta; often mosaic

Question 37

XXX, XXXX, etc.

Answer 37

Increased # = increased MR

Question 38

Hermaphroditism

Answer 38

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)

Question 39

Testicular feminization

Answer 39

XY with no androgen receptors but normal testosterone levels; beautiful, long-legged, symmetrical, no menstruation because no uterus or cervix, blind vagina

Question 40

Fragile X syndrome

Answer 40

Triplet repeats of CGG, Xq27; oogenesis, MR, long face, large mandible, large everted ears, macroorchidism, anticipation

Question 41

Huntington's Disease

Answer 41

CAG triplet repeats, AD

Question 42

Friedrich's Ataxia

Answer 42

GAA triplet repeats on chr 9 FRDA gene for Frataxin; gait then all limb ataxia, puberty onset, in wheelchair by 25, death by cardiomyopathy

Question 43

Prader-Willi syndrome

Answer 43

Deletion at paternal 15q12 or maternal disomy 15; short, fat, male, MR

Question 44

Angelman syndrome

Answer 44

Deletion at maternal 15q12 or paternal disomy 15; severe MR, very happy