Typical and Atypical Mendelian Inheritance

Question 1

What are the 4 types of typical Mendelian inheritance?

Answer 1

Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive

Question 2

What are the 4 types of atypical Mendelian inheritance?

Answer 2

Genetic anticipation
Pseudo-dominant inheritance
Mitochondrial inheritance
Pseudo-autosomal inheritance

Question 3

Give 4 examples of autosomal dominant disorders.

Answer 3

Achondroplasia
Hereditary breast/colon cancer
Autosomal dominant polycystic kidney disease (ADPKD)
Neurofibromatosis type 1 (NF1)

Question 4

List 3 features of autosomal dominant inheritance on family trees.

Answer 4

Vertical transmission pattern (i.e. every generation is affected)

Males and females equally affected

Father-son transmission

Question 5

What is variable expression?

What causes it?

Give 1 example of this.

Answer 5

AD conditions in which individuals within the same family can be affected to different extents

CAUSED BY: modifier genes

EXAMPLE: FGFR2 gene in BRCA2 mutations

Question 6

How do you tell the difference between autosomal and X-linked dominant disorders?

The two can look very similar.

Answer 6

Father-son transmission

Autosomal: present

X-linked: not possible, because fathers pass on Y chromosome to sons

Question 7

List 4 other features of autosomal dominant disorders.

Give a brief description of each.

Answer 7

Variable expression

• Caused by modifier genes
• Individuals within the same family can be affected to different extents

Incomplete penetrance

• Caused by modifier genes
• Individuals who are unaffected due to incomplete penetrance can still pass on the mutation and have affected children

Complete penetrance

• Mutation will definitely cause disease
• E.g. achondroplasia

Gonadal mosaicism

• Caused by new mutations in some egg/sperm cells in unaffected individuals
• These (unaffected) parents will have a slightly higher risk of having affected children

Question 8

Give 5 examples of autosomal recessive disorders.

Answer 8

Sickle cell anaemia
Cystic fibrosis
Phenylketonuria (PKU)
Spinal muscular atrophy (SMA)
Congenital adrenal hyperplasia (CAH)

Question 9

List 3 features of autosomal recessive disorders on family trees.

Answer 9

Horizontal patterns (i.e. affected individuals within same generation)

Males and females affected equally

Consanguinity

Question 10

List 3 other features associated with autosomal recessive disorders.

Give a brief description of each.

Answer 10

Carriers
-Heterozygous individuals carrying one affected gene, which isn’t enough to cause disease

Compound heterozygotes
-There are 2 mutated alleles, but each allele contains a different mutation

Complete penetrance
-If the mutations are present, the individual will always have the disease

Question 11

Give 2 examples of X-linked recessive disorders.

Answer 11

Duchenne muscular dystrophy (DMD)

Becker’s muscular dystrophy (BMD)

Question 12

List 4 features of X-linked recessive disorders on family trees.

Answer 12

Knights move pattern (affected males and affected uncles)

No male-male inheritance

Mostly (or only) males affected

Manifesting carriers

Question 13

What are manifesting carriers?

What is the cause of this?

Answer 13

Female carriers who present with an X-linked recessive disorder, despite only having 1 mutated X chromosome.

Caused by: skewed X inactivation (i.e. too many health X chromosomes are inactivated)

Question 14

List 3 examples of X-linked dominant disorders.

Which of these are always fatal for males?

Answer 14

Vitamin D resistant rickets

Incontinentia pigmenti (male lethality)

Rett syndrome (male lethality)

Question 15

List 3 features of X-linked dominant disorders on family trees.

Answer 15

Vertical pattern

Mostly females affected

No male-male transmission

Question 16

Give 3 examples of disorders showing genetic anticipation.

Answer 16

Huntington’s disease
Fragile X syndrome
Myotonic dystrophy

Question 17

Give 1 example of a disorder with pseudo-dominant inheritance.

What is the carrier frequency for this disorder?

Answer 17

Gilbert’s syndrome (carrier frequency 50-60%)

Question 18

Give 1 example of mitochondrial inheritance.

Answer 18

Leigh syndrome

Question 19

List 2 features of disorders with mitochondrial inheritance.

Answer 19

Variable expression

Only inherited from mother (because egg cell passes on mitochondria, sperm cell does not)

Question 20

Define “pseudo-autosomal inheritance”.

Answer 20

X-linked inheritance which appears as an autosomal dominant condition, due to the fact that the mutation is found on a region of the X chromosome that is commonly joined onto the Y chromosome (a pseudo-autosomal region, PAR1 or PAR2)

Question 21

Give 1 example of a disorder caused by pseudo-autosomal inheritance.

Answer 21

Leri-Weill dyschondrosteosis

Question 22

Describe the pathophysiology of pseudo-autosomal inheritance. (2)

Answer 22

1. The PAR1 and PAR2 regions of the X chromosome frequently attach to the Y chromosome (i.e. undergo recombination)
   - This is NORMAL
2. When there is a mutation in PAR1 or PAR2, this mutation will be inherited in a way that appears autosomal, due to the fact that it is on both the X and Y chromosome