Autosomal Dominant Disorders

Question 1

Autosomal Dominant (4) characteristics

Answer 1

1. Manifested in homozygotes and heterozygotes
2. Maps to an autosome
3. Equal in males and females
4. Can be passed by either parent

Question 2

Achondroplasia is an _____ disorder with ______ penetrance and an ____% new mutation rate.

Answer 2

Autosomal dominan; complete; 80%

Question 3

1: ____ live births with achondroplasia?

Answer 3

1:15,000-40,000

Question 4

Clinical Manifestations of Achondroplasia?

Answer 4

Small stature        Males 4’ 3”     Females 4’
Rhizomelic limb shortening
Short fingers
Genu varum
Trident hands
Large head/frontal bossing
Midfacial retrusion
Small Foramen Magnum/Craniocervical instability

Question 5

Achondroplasia is a mutation on chromosome ____ at gene locus _____ that affects the gene called _____ which encodes for a protein called _____ which has the function of______. Increase/decrease of this protein interferes with _____?

Answer 5

Chromosome 4; 4p16.3; FGFR3; Fibroblast Growth Factor Receptor 3; Regulates bone growth by limiting the formation of bone from cartilage. Increase in the activity of this protein interferes with skeletal development.

Question 6

What is the amino acid substitution at the p16.2 locus of chromosome 4 that causes achondroplasia? What is unique about this mutation?

Answer 6

Gly—->Ala. Nucleotide 1138 of the FGFR3 gene has the highest new mutation rate known in man.

Question 7

Paternal Age Effect

Answer 7

Men over the age of 40 are noted to have a higher rate of children with de-novo autosomal dominant conditions. Large number of cell divisions during spermatogenesis increases the mutation rate. Older men have decreased ability to repair mutations

Question 8

Pure Dominant

Answer 8

Homozygotes and Heterozygotes are both equally affected

Question 9

Incompletely Dominant

Answer 9

Homozygotes are affected more severely

Question 10

Neurofibromatosis Type 1 is an AD disorder affecting _____ (ratio) live births with a ____ mutation rate.

Answer 10

1/3000; 50%

Question 11

What are diagnostic symptoms of neurofibromatosis?

Answer 11

6 or more café-au-lait spots
2 or more neurofibromas 
1 plexiform neurofibroma
Freckling in the axillary or inguinal area
Optic glioma
2 or more Lisch Nodules
Distinctive osseous lesions
Affected first degree relative

Question 12

Neurofibromatosis is caused by a mutation on chromosome ____ at gene locus _____ that affects the gene called _____ which encodes for a protein called _____. This a mutation that causes ______.

Answer 12

Chromosome 17; 17q11.2; NF1; Neurofibromin; loss of function of protein

Question 13

Marfan Syndrome is an AD disorder with a _____ new mutation rate that affects _____ (ratio) live births

Answer 13

25% new mutation rate; 1 in 5000 births

Question 14

Clinical Manifestations of Marfan’s (3 big categories)

Answer 14

Systemic disorder of connective tissue

1. Ocular
2. Skeletal
3. Cardiovascular

Question 15

Diagnosis of Marfan’s syndrome?

Answer 15

w/o family history 
Aortic root enlargement (+)
Ectopia Lentis or
FBN1 mutation or
Systemic score >7

w/family history
Ectopia Lentis
Systemic score of >7
Aortic root enlargement

Question 16

Marfan’s is caused by a mutation on chromosome ____ at gene locus _____ that affects the gene called _____ which encodes for a protein called _____ which is inccorporated into the _____. This a mutation that is ______, and results in_____ .

Answer 16

Chromosome 15; 15q21.1; FBN1; Fibrillin 1; extracellular matrix; dominant negative (gene product adversely affects normal gene product); severe reduction in number of microfibrils

Question 17

Autosomal Dominant Polycystic Kidney Disease has a ____% new mutation rate, and affects ____ (ratio) live births?

Answer 17

5%; 1/1000

Question 18

Clinical Manifestations of Autosomal Dominant Polycystic Kidney Disease?

Answer 18

Bilateral renal cysts
Cysts in other organs
Vascular abnormalities
End stage renal disease in 50% by 60 years old

Question 19

What are the mutations/gene products/defects involved in Autosomal Dominant Polycystic Kidney Disease?

Answer 19

PKD1 chromosome 16p13.3
PKD2 chromosome 4q22.1 (15%)
Polycystin 1 and 2
Produces a truncated protein

Question 20

Familial Hypercholesterolemia occurs in ____ (ratio) live births, with a ___ mutation rate (non-numeric).

Answer 20

1/200-500; very low

Question 21

Clinical Manifestations of Familial Hypercholesterolemia will show LDL of ____, and total cholesterol of _____. They may have subcutaneous accumulation of cholesterol called _____ and die from _____.

Answer 21

> 190; >310; xanthomas; premature coronary artery disease

Question 22

Mutations in 3 genes known to cause Familial Hypercholesterolemia:

Answer 22

LDLK
APOB
PCSK9