Autosomal Dominant Diseases

Question 1

What are the clinical manifestations of achondroplasia?

Answer 1

Small stature (4’ female - 4’3 male); rhizomelic limb shortening; short fingers; genu varum; trident hands; midfacial retrusion; small foramen magnum

Question 2

What is the mutation seen in achondroplasia?

Answer 2

Mutation on FGFR3 (fibroblast growth factor receptor 3) on chr. 4p16.3; nucleotide 1138. Amino acid substitution-missense mutation; Gly380Arg. Mutation increases the activity of the protein interfering with skeletal development

Question 3

Which nucleotide on which gene has the highest mutation rate known in man?

Answer 3

Nucleotide 1138 of the FGFR3 gene

Question 4

Are Pts with achondroplasia heterozygotes or homozygotes?

Answer 4

Must be heterozygotes b/c homozygotes are incompatible with life (incompletely dominant).

Question 5

Which gene on which chromosome is mutated in retinoblastoma?

Answer 5

RB1 gene on chromosome 13 (90% penetrance)

Question 6

Pts must have 2 or more of the following to be diagnosed with Neurofibromatosis Type I

Answer 6

6 or more cafe-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 7

What is the mutation seen in neurofribromatosis type I (gene and chromosome)? What type of mutation is this?

Answer 7

NF1 (neurobibromin-tumor suppressor gene) on chr.17q11.2. Since this is a tumor supressor gene; this is a loss of function mutation

Question 8

Is neurofibromatosis dominant or recessive? Why is this kind of weird?

Answer 8

Dominant but weird because the Pt must also have a mutation in the cells involved to show the phenotype

Question 9

What does locus heterogeneity mean?

Answer 9

A mutation in more than one locus causing the same clinical condition

Question 10

Describe inheritance; rate; expressivity; penetrance of tuberous sclerosis

Answer 10

Autosomal dominant; 1/6000; variable expressivity; fully penetrant; 1/3 inherited 2/3 d novo

Question 11

What skin findings might you expect with tuberous sclerosis?

Answer 11

Hypopigmented Patches; Angiofibroma; Shagreen Patch; Ungual fibroma

Question 12

What kindey findings are expected with tuberous sclerosis?

Answer 12

Renal cysts; renal angiomyolipomas

Question 13

What lung findings are expected with tuberous sclerosis?

Answer 13

lympangioleiomyomatosis

Question 14

What heart findings are expected with tuberous sclerosis?

Answer 14

Cardiac rhabdomyoma (in infants)

Question 15

What CNS findings are expected with tuberous sclerosis?

Answer 15

Subependymal nodules; Subependymal giant cell astrocytomas (SEGAs); Other cortical dysplasias; seizures

Question 16

What neuropsychiatric disorders are expected with tuberous sclerosis?

Answer 16

Cognitive impairment; Autism; ADHD; Other behavioral and emotional problems

Question 17

What are the clinical criteria to be diagnosed with tuberous sclerosis?

Answer 17

Two major features or 1 major feature with 2 minor features

Question 18

What are the major features with tuberous sclerosis (11)?

Answer 18

Angiofibromas; Cardiac rhabodmyoma; Cortical dysplasias; Hypomelanotic macules; Lymphangioleiomyomatosis; Multiple retinal nodular hamartomas; Renal angiomyolipoma; Shagreen Patch; Subependymal nodule; SEGA; Ungual Fibroma

Question 19

What are the minor features with tuberous sclerosis (6)?

Answer 19

Confetti skin lesions; Dental Enamel pits (>3); Intraoral fibromas; Multiple renal cysts; Nonrenal hamartomas; Retinal achromic patch

Question 20

What is the mutation in tuberous sclerosis (gene and chromosome)? There are 2 possible

Answer 20

TSC1; TSC2 genes. On chromosome 9 and 16. Only need a mutation in 1 of the genes; but a mutation in either gene will cause disease

Question 21

What do TSC1 and TSC2 do? What type of mutation is there is tuberous sclerosis?

Answer 21

Encode hamartin and tuberin proteins; Regulate cell growth and proliferation. Loss of function mutations

Question 22

What are the clinical manifestations of osteogenesis imperfecta type 1?

Answer 22

Multiple fractures; Mild short stature; Adult onset hearing loss; Blue sclera

Question 23

What is the mutation seen with osteogenesis imperfecta type 1 (gene and chromosome)?

Answer 23

COL1A1 (collagen type 1 alpha 1) on chr. 7q21.3

Question 24

What occurs with the mutation seen in osteogenesis imperfecta type 1?

Answer 24

Reduced production of pro-alpha 1 chains that reduces the type 1 collagen production by half

Question 25

What are the clinical manifestations in marfan syndrome?

Answer 25

Systemic disorder of connective tissue; Ocular; Skeletal; Cardiovascular. Note that connective tissues are also part of the vascular system; most importantly in the large arteries

Question 26

What is needed to make a diagnosis of Marfan syndrome with and without a family history?

Answer 26

No family history: Aortic root enlargement + ectopia lentis; FBN1 mutation; or sytemic score >7. Positive family history only need 1 out of: ectopia lentis; systemic score >7; aortic root enlargement

Question 27

What is the mutation seen in marfan syndrome (gene and chromosome)?

Answer 27

FBN1 (fibrillin-extracellular matrix protein) on chr. 15q21.1

Question 28

What is the immediate effect of the mutation seen in marfan syndrome?

Answer 28

Severe reduction in the number of microfibrils

Question 29

What is a trinucleotide repeat disorder?

Answer 29

Expansion of a segment of DNA consisting of three or more nucleotides

Question 30

What kind of transmission is seen in a trinucleotide repeat disorder?

Answer 30

AD; AR; and X-linked transmission

Question 31

What is slipped mispairing?

Answer 31

Mispairing of bases in regions of repetitie DNA replication plus inadequate DNA repair systems

Question 32

What is anticipation?

Answer 32

When the severity and/or onset of disease increases in the next generation. Seen in trinucleotide repeat disorders

Question 33

What is parental transmission bias?

Answer 33

When the trinucleotide expansion is more prone to occur in gametogenesis of the male or female

Question 34

What kind of inheritance is seen in huntington disease? Rate?

Answer 34

AD; 1 in 10;000

Question 35

What kind of mutation is huntington disease?

Answer 35

It is a trinucleotide repeat disorder (CAG)

Question 36

What does the parent of origin have to do with the expression of the disease in huntingtons?

Answer 36

If inherited through father more likely to be early onset; if inherited through mother more likely to be later onset

Question 37

What are the clinical manifestations of huntington disease?

Answer 37

Progressive neuronal degeneration. Causes motor; cognitive; psychiatric distrubances. Age of onset 35-44. Death about 15 years after onset

Question 38

On which gene/chromosome is the hungtington mutation?

Answer 38

HTT (Huntington gene) on chr. 4p16.3

Question 39

What may cause the biochemical property/altered structure of the protein in Hungtinton?

Answer 39

The expansion of glutamine

Question 40

What is the repeat count and classification/disease status for CAG repeat disorders (huntington)?

Answer 40

39: full penetrance and affected. >60: juvenile onset and affected

Question 41

What other AD trinucleotide repeated disorder did we learn about besides Huntingtons?

Answer 41

Myotonic Dystrophy Type 1

Question 42

Which trinucleotide sequence is repeated in Myotonic Dystrophy Type 1?

Answer 42

CTG

Question 43

What is the rate and type of transmission seen in MD type 1?

Answer 43

1 in 20000. Maternal transmission. Seen with anticipation

Question 44

What are the clinical manifestations of myotonic dystrophy type 1?

Answer 44

Adult onset muscular dystrophy; Progressive muscle wasting and weakness; Myotonia; Cataracts; Cardiac conduction defects

Question 45

Where is the mutation seen in myotonic dystrophy type 1? Gene and chromosome?

Answer 45

DMPK gene (myotonic dystrophy protein kinase) on chr. 19q13.3. Plays important role in muscle; heart; brain cells

Question 46

What is the CTG repeat count and range of disease seen with myotonic dystrophy type 1?

Answer 46

5-34: Normal. 34-49: premutation range. >50 full mutation with 100% penetrance