Clinical genetics in medical practice 1

Question 1

Define Karyotype

Answer 1

The number and visual appearance of the chromosomes in the cell nuclei of an organism or species

Question 2

Define mutation

Answer 2

A pathogenic(heritable) alteration in the gene affecting the structure or the function of a protein.

Question 3

What are the characteristics of autosomal dominant conditions

Answer 3

• Caused by a mutation in a single autosomal gene
• Affected individuals are heterozygous for the mutation
• They have a normal(wild) type and a mutant copy of the gene
• Transmitted from generation to generation( i.e vertical inheritance)
• Males and females are usually affected equally
• Affected parent of either sex can transmit the disorder to both sons and daughters
• 1 in 2 (50%) risk of an affected parent transmitting the condition to his/her children
• Key feature= male-to-male transmission
• Variable (reduced) penetrance
• Variable expression

Question 4

What is reduced penetrance?

Answer 4

• Penetrance is a statistic and is usually expressed as a %
• The proportion of carriers who manifest phenotypic signs of the condition
• Not all individuals who inherit a dominant disease mutation necessarily show signs of the condition
• There may be age-specific penetrance

Question 5

What are some of the characteristics of cherubism and its inheritance?

Answer 5

• A genetic abnormality
• Occurs as an autosomal dominant disorder and with 100% pentrance in males and 50 to 75% penetrance in females with 2:1 male predominance
• Marked fullness of the jaws

Question 6

What is variable expression/ expressivity?

Answer 6

• Extent of clinical manifestation

- Variable within and between families

Question 7

What are the 4 defects in Tetralogy of Fallot?

Answer 7

-Thick right ventricle (hypertrophy)
-Ventricular septal defect (VSD)
-Pulmonary stenosis(narrow pulmonary valve)
-Large overriding aorta.
This leads to reduced pulmonary blood flow due to a narrow outlet

Question 8

What is germline mosaicism?

Answer 8

A parent carries a small proportion of gametes(germline cells) that harbour the same mutation

Question 9

What are the characteristics of autosomal recessive conditions?

Answer 9

• Males and females can be equally affected
• Generally only members of a single sibship, or cousins affected(unless multiple consanguinity in the family)
• The probability that a future sibling of an affected individual will also be affected is 1 in 4
• The probability that a future sibling will be a carrier is 1 in 2
• The probability that an existing unaffected sibling is a carrier is 2 in 3 (the denominator changes as we have excluded the affected individual from our calculation)

Question 10

What is compound heterozygosity?

Answer 10

-Someone who has different allelic mutations at the same locus

Question 11

What are the characteristics of X-linked recessive disorders?

Answer 11

• Only males related via the female line are usually affected
• Women are usually asymptomatic
• 1 in 2 chance that each son born to a carrier female will be affected
• 1 in 2 chance that each daughter will be a carrier
• All the daughters of an affected male will be carriers
• Sons of an affected male are not affected (no male-male transmission)

Question 12

How can females be affected with X-linked recessive disorders?

Answer 12

• Non-random inactivation leading to chance expression in certain tissues e.g expression of mutant allele in: heart in Duchenne Muscular dystrophy carriers; Kidney in X-linked Alport’s disease; brain in fragile X syndrome(learning disability)
• Turner’s syndrome 45,X

Question 13

What is X inactivation?

Answer 13

• Only one X used per cell in 46 XX or 47XXY
• Idea of dosage compensation
• One X in each cell is switched off before blastocyst implants in females
• All women are mosaics, expressing either their maternal or paternal X but not both in any one of their cells

Question 14

Explain the idea of random X inactivation

Answer 14

• One X chromosome per cell is inactivated by methylation
• All of its daughter cells have the same X chromosome inactivated (i.e they are a clone of cells with the same pattern of inheritance)

Question 15

What are the characteristics of X-linked dominant disorders?

Answer 15

• Males and females affected (males>females)
• Affected females can show a mosaic pattern of involvement in tissues such as skin
• The condition may be lethal in males
• 50% offspring risk to males and females of affected mothers
• All daughters of affected males inherit the condition
• None of the sons of affected males inherit the condition.

Question 16

What are lines of Blaschko

Answer 16

• represent territories of clonal cell populations: some using normal X chromosome, some using mutated X chromosome
• Can be manifest in X-linked dominant disorders e.g Incontinentia Pigmenti and Goltz focal dermal Hypoplasia.