Lecture 6 - Patterns of inheritance I

Question 1

• X-linked recessive disorder
• Due to mutations in the gene that codes for the protein dystrophin
• gross motor developmental-delay, low muscle tone, weakness (classic sign is using arm to push on leg after picking something off the floor)
• muscle biopsy is disorganized
• female carriers can have elevated CPK, weakness, or cardiac issues

Answer 1

Duchenne muscular dystrophy

Question 2

Variable expression

Answer 2

Different degrees of clinical expression given the same genotype

Question 3

Penetrance

Answer 3

The proportion of individuals who harbor a specific mutation who clinically express the effect of it

Question 4

• cafe-au-lait spots
• axillary/inguinal freckling
• benign tumors (including Lisch nodules, optic gliomas, and neurofibromas)
• bony displasias
• complete penetrance

Answer 4

Neurofibromatosis

Question 5

• connective tissue disorder caused by mutations in the microfibrillar protein, fibrillin

Cardinal clinical features:

• skeletal: arachnodactyly, dolichostenomelia, joint laxity
• cardiac: dilation/rupture of aorta
• cutaneous: easy bruising, poor wound healing
• ocular: lens dislocation, myopia, keratoconus
• complete penetrance

Answer 5

Marfan Syndrome

Question 6

• penetrance estimated @ 80%
• variable expression
• cleft palate
• lip pits in lower lip

Answer 6

van der Woude syndrome

Question 7

Pleiotropism

Answer 7

multiple clinical effects of a single gene

e. g. Kabuki syndrome

Question 8

Genetic Heterogeneity

Answer 8

Different mutations causing an identical or similar phenotype

Allelic heterogeneity refers to a different mutations at the same locus

Locus heterogeneity refers to mutations at different loci

Question 9

Spinocerebellar Ataxia

Answer 9

Progressive degeneration of cerebellum and brainstem

Example of locus heterogeneity

Question 10

Paternal age effect

Answer 10

Increased incidence of new (sporadic) dominant mutations in association with advanced paternal age (>45)

E.g. Achondroplasia - most freq. form of short-limb dwarfism

Others:

• marfan syndrome
• neurofibromatosis
• Treacher-Collins syndrome
• Crouzon syndrome
• progeria

Question 11

Effects of consanguinity

Answer 11

Increases risk of AR disorders

Risk above baseline (3-4%):

• 3rd degree relatives - 2-3%
• 2nd degree relatives - 5-15%
• 1st degree relatives - 40%