Genetics

Question 1

What is the cystic fibrosis mutation?

Answer 1

CFTR on chromosome 7q31.2

Autosomal recessive

Question 2

What is the most common mutation in alpha1-antitrypsin deficiency?

Answer 2

PIZZ

High risk for hepatocellular carcinoma and emphysema

Question 3

What is thalassemias and what causes them?

Answer 3

Mutation in globin gene affects amount of globin chains synthesized

Question 4

What kind of adverse drug reaction do G6PD def patients have?

Answer 4

Adverse reaction to antimalarial drug primaquine. Leads to severe hemolytic anemia.

Question 5

What is the most common mutation seen in Marfan syndrome? How does it manifest?

Answer 5

AD, FBN1 Chr 15Q21.1

Defect in extracellular glycoprotein, fibrillin-1, leads to loss of structural support and excessive activation of TGF-beta signaling.

Question 6

What gene defects cause classic E-D syndrome (type I and II)?

Answer 6

COL5A1 and COL5A2

Question 7

What gene defect causes vascular E-D syndrome (type IV)?

Answer 7

COL3A1

Question 8

What gene defect causes kyphoscoliosis E-D syndrome (type VI)?

Answer 8

Lysyl hydroxylase

Question 9

What is the enzyme deficiency in Tay-Sachs? What does this lead to an accumulation of?

Answer 9

Hexosaminidase A deficiency

Leads to accumulation of GM2 ganglioside

Question 10

What is the enzyme deficiency in Gaucher? What does this lead to an accumulation of?

Answer 10

Glucocerebrosidase deficiency (chr 15)

Leads to accumulation of glucocerebroside

Question 11

What is the enzyme deficiency in Niemann-Pick? What does this lead to an accumulation of?

Answer 11

Sphingomyelinase deficiency

Leads to accumulation of sphingomyelin

Question 12

What is the enzyme deficiency in MPS I Hurler? What does this lead to an accumulation of? How is it inherited?

Answer 12

alpha-L-iduronidase deficiency (autosomal recessive)

Leads to accumulation of dermatan sulfate and heparan sulfate

Question 13

What is the enzyme deficiency in MPS II Hunter? What does this lead to an accumulation of? How is it inherited?

Answer 13

L-Iduronosulfate sulfatase deficiency (X-linked recessive)

Leads to accumulation of dermatan sulfate and heparan sulfate

Question 14

What are some hallmarks for Tay-Sachs?

Answer 14

Ashkenazic Jews. Motor and mental defects start to manifest at 6 mo. Cherry red spot in macula. Death by 2-3 years.

Question 15

What are some hallmarks for Niemann-Pick?

Answer 15

Ashkenazic Jews. Severe neuro damage in type A. No neuro damage in type B. Progressive neuro damage in type C. Zebra bodies. Massive splenomegaly. May have cherry red spot.

Question 16

What are some hallmarks for Gaucher?

Answer 16

No CNS involvement in type I, jewish, 90% of cases. Acute neuronopathic in type II, not jewish, early death. Intermediate CNS involvement in type III.

Distended phagocytic gaucher cells in liver, spleen, and BM. Enlarged spleen. Pancytopenia or thrombocytopenia. “Crumpled tissue paper”

Question 17

What are some hallmarks for Hurler vs Hunter?

Answer 17

Hurler: AR. Norm at birth, death by 6-24 due to cardiovascular complications. Clouding of the cornea.

Hunter: X-linked. No corneal clouding. Milder.

Both have zebra bodies and balloon cells (PAS+). Both have hepatosplenomegaly.

Question 18

What is a hepatic form of glycogenoses? What are the hallmarks of it?

Answer 18

Von Gierke. Glucose-6-phosphatase def. High glycogen in liver, low blood glucose.

Question 19

What is a myopathic form of glycogenoses? What are the hallmarks of it?

Answer 19

McArdle dz. Muscle phosphorylase def. High glycogen storage in muscle and muscle weakness. No increase in blood lactate after exercise.

Question 20

What type of glycogenoses has a acid maltase def?

Answer 20

Pompe dz. Leads to cardiomegaly.

Question 21

What is a Robertsonian translocation?

Answer 21

Centric fusion. Translocation between 2 acrocentric chromosomes, typically breaks appear closer to the centromeres. Leads to 1 very large chromosome and an extremely small one that is usually lost. Typically has normal phenotype. Can lead to Trisomy 21 if 3 copies of long arm of chr 21.

Question 22

What are the main hallmarks of trisomy 21?

Answer 22

Epcanthic folds. One long crease in palm. 40% have congenital heart disease, most commonly defect in endocardial cushion and/or septal defects. Risk of developing acute leukemia. Develop changes characteristic of alzheimers. Abnormal immune responses lead them predisposed to serious infections.

Question 23

What are some hallmarks of Edwards (trisomy 18)?

Answer 23

Renal malformations, mental retardation, rocker bottom feet. Limited hip abduction.

Question 24

What are some hallmarks of patau syndrome (trisomy 13)?

Answer 24

Cleft lip and palate. Polydactyly. Renal defects. Mental retardation. Rocker-bottom feet. Umbilical hernia.

Question 25

What are the hallmarks of Chr 22q11.2 deletion syndrome?

Answer 25

Congenital heart defects, abnormalities of the palate, facial dysmorphism. Variable degrees of immunodeficeincy and hypocalcemia.

Question 26

What are the two main types of Chr 22q11.2 deletion syndrome and their differences?

Answer 26

DiGeorge syndrome: Thymic hypoplasia with T cell immunodeficiency, parathyroid hypoplasia. Leads to hypocalcemia and cardia malformations. Mild facial anomalies. CATCH 22 Velocadiofacial syndrome: facial dysmorphism, cleft palate, cardiovascular anomalies, learning disabilities.

Question 27

What is the genotype and hallmarks of Klinefelter syndrome?

Answer 27

47, XXY. Male hypogonadism. Not dx until puberty. High risk for DM2 and metabolic syndrome. Risk for mitral valve prolapse, osteoporosis, and fractures. Lack of secondary male characteristics. Male infertility. High risk of breast cancer and autoimmune diseases.

Question 28

What is the genotype and hallmarks of Turner syndrome?

Answer 28

45, XO. Female hypogonadism (most common). Can be complete or partial monosomy, partial is more common. Congenital heart disease, bicuspid aortic valves. Short stature. Menopause occurs before menarche. STREAK OVARIES. Half develop antibodies to thyroid leading to hypothyroidism. Obesity is common. Most common cause of primary amenorrhea. Cystic hygroma: infant with edema, swelling of the nape of the neck due to lymph stasis. Leads to bilateral neck webbing.

Question 29

What kind of mutation causes fragile X syndrome?

Answer 29

Trinucleotide repeat mutation leading to a loss of function (non-coding region). CGG triplet. X-linked recessive.

Question 30

What kind of mutation causes Huntington disease?

Answer 30

Trinucleotide repeat mutation leading to toxic gain of function (coding region). CAG triplet. Autosomal dominant. Chromosome 4.

Question 31

What kind of mutation causes fragile X tremor-ataxia syndrome?

Answer 31

Trinucleotide repeat mutation leading to toxic gain of function mediated by mRNA (noncoding region). CGG triplet.

Question 32

What is the morphologic hallmark seen in all trinucleotide repeat mutations?

Answer 32

Accumulation of aggregated mutant proteins in large intranuclear inclusions.

Question 33

What are the hallmarks of fragile X syndrome?

Answer 33

Second most common cause of mental retardation after down. More common in males. Long face, large mandible, large elevated ears, hyperextensible joints, high arched palate. Most distinctive feature is macro-orchidism (large testicles)

Question 34

What are some of the atypical patterns of transmission seen in fragile x syndrome.

Answer 34

20% of males can by clinically and cytogenetically normal. More repeats seem to be added during oogenesis, so it is amplified in female offspring. 30-50% of carrier females are affected. Anticipation: Clinical features of fragile x worsen with each successive generation.

Question 35

What are the hallmarks of huntington disease?

Answer 35

Jerky movements. Rigidity. Atrophy of brain. Repeat expansions occur during spermatogenesis, so onset is earlier with each generation. (anticipation).

Question 36

What is heteroplasmy?

Answer 36

Tissues and individuals that harbor both wild type and mutant mtDNA.

Question 37

What is leber hereditary optic neuropathy (LHON) and how is it inherited?

Answer 37

Neurodegenerative disease that manifests as progressive bilateral loss of central vision. Also has cardiac conduction defects and minor neurologic manifestations. mtDNA disorder.

Question 38

What is the difference in inheritance between Angleman and Prader-Willi?

Answer 38

Angleman: deletion in maternal chromosome with paternal imprint. Prader-Willi: deletion in paternal chromosome with maternal imprint. In both cases, this leads to nonfunctioning alleles in both chromosomes (15q11.2-q13)

Question 39

What are the symptoms seen in Angleman and Prader-Willi?

Answer 39

Angleman: Mental retardation, ataxic gait, seizures, and inappropriate laughter. "Happy puppets" Prader-Willi: Mental retardation, short stature, hypotonia, profound hyperphagia, obesity, small hands/feet, and hypogonadism.