Single-Gene Disorders

Question 1

How can you identify a autosomal dominant inheritance in a pedigree?

Answer 1

• disease in multiple generations
• if penetrance isn’t low - rare to see skip generations
• man and women equally affected

Question 2

Recurrence risk of a autosomal dominant inheritance

Answer 2

• 50% if one parent affected (Aa classically)

- 75% if both parents heterozygous affected

Question 3

How do you identify an autosomal recessive inheritance pattern?

Answer 3

• usually only see the affected one generation
• equally man and women affected
• offspring must inherit one copy of the disease allele from each parent
• RR=25% (both heterozygous carriers)

Question 4

Do the sexual chromosomes have homologous chromosomes or regions?

Answer 4

Yes, although most regions are different, even in man spermatogenesis X and Y have homologous regions ▶️ pseudo autosomal regions, pair them on it ▶️ segregation in different cells

Question 5

How do you identify a X-linked recessive inheritance?

Answer 5

• only male typically will be affected (“hemizygous for X chromosome)
• skip generations
• not seen male to male transmission (difference from autosomal)
• RR depend of the fetus or offspring sex

Question 6

What mechanism are associated with X inactivation?

Answer 6

• XIST: produces a RNA product that coats the chromosome
• heterochromatin: condensation
• methylation gene regions

Question 7

How do you identify a X-linked dominant disease, classic example and RR?

Answer 7

• Fragile X syndrome, Hypophosphatemic rickets
• no male-male transmit
• 2 times woman>men, heterozygous affected
• multiple generations, skip them is unusual
• penetrance males 100%, female 60%
• RR: depends of the sex

Question 8

Characteristics of mitochondrial inheritance

Answer 8

• both male and female affected
• only transmission from female
• offspring from affected male won’t be affected
• typically myopathies and/or neuropathies

Question 9

What causes the variation in the severity of expression of mitochondrial diseases

Answer 9

Heteroplasmy

Question 10

Which are the factors that can contribute to a variable expression?

Answer 10

• environmental influences
• allelic heterogeneity
• Heteroplasmy
• modifier loci

Question 11

What disease show incomplete penetrance as well as variable expression, what is its mode of inheritance?

Answer 11

Hemochromatosis

- autosomal recessive, penetrance 15%

Question 12

What disease classically must develop a second mutation to complete a 90% of penetrance, and that its mode of inheritance is autosomal dominant?

Answer 12

Retinoblastoma

Question 13

Difference between no penetrance and variable expression

Answer 13

No penetrance have no symptoms in all, variable expression is a gamut from less to more severe symptoms

Question 14

Why Marfan syndrome show pleitropy?

Answer 14

Fibrilin expression in periosteum, perichondrium, suspensory ligament of eye, aorta

Question 15

What is the cause of prader-willi and Angelman syndrome?

Answer 15

Deletion of “supposed” active gene, and leave the inactive normal imprinted gene