W6-Lecture 4.1 - Principles of Mendelian Inheritance - part 1

Question 1

What is X-linked inheritance?

Answer 1

Disoders coded by genes on the sex chromosome. They can be dominant or recessive X-linked disoders.

*Note: we have autosomal linked disoders (arising from autosomes) and X-linked disoders (from sex chromosomes)

Question 2

What is X chromosome inactivation?

Answer 2

• The random silencing of one of the 2 sex chromosomes only on females.
• There is complete suppression of gene expression on one of the 2 X chromosomes
• The inactivation occurs during early embryonic development.

*The reason is to balance gene expression between males and females, considering males have one X while females have 2.

Question 3

What is skewed X chromosome inactivation?

Answer 3

• The non random inactivation of one of the 2 X chromosomes on females. One X is preferentialy inactivated.
• The inactivated X is not completely suppressed. It still expresses its genes in low rates though.
• This phenomenon leads to an imbalance in gene expression between the two X chromosomes. This can have effects similar to those seen in X-linked genetic disorders, where one copy of a gene is non-functional due to mutation.

Question 4

Features of an X-linked dominant inheritance

Answer 4

• Disease present in every generation
• Affects both males and females
• Both males and females transmit the defective gene
• More miscarriages are associated with women presenting with X-linked dominant inheritance

*Males transmit to their daughters but NEVER to their sons

Question 5

Features of an X-linked recessive inheritance

Answer 5

• Appearence of generation skipping
• Usually only manifest on males
• Affected males are hemizygous for the mutant allele. (males with one copy of the mutated gene)
• Females transmit to males
• Males transmit to females (obligate carriers)
• No male-to-male transmission

*Males transmit to their daughters but NEVER to their sons

Question 6

What does hemizygous mean? Who are prone to this, and why?

Answer 6

• Hemizygous means u have one copy of a gene.
• Males are prone to it.
• They have one X chromosome compared to females who have 2 X chromosomes. Having 2 X chromosomes mean you have 2 copies of the gene, one copy on the other X, and another copy on another X.

Question 7

Name example of an X-linked recessive disorder

Answer 7

Duchenne muscular atrophy

Question 7

Name examples of X-linked dominant disoder

Answer 7

• X-linked hypophosphatemic rickets (Vitamin D resistant rickets)
• Incontinentia pigmenti
• Rett syndrome
• Goltz syndrome
• Craniofrontonasal syndrome

Question 8

Most common and severe form of childhood muscular dystrophy, mostly seen in boys.

Answer 8

Duchenne muscular atrophy

Question 9

Features of Duchenne muscular dystrophy

Answer 9

• Characterized by progressive, symmetrical muscle weakness
• Symptoms start before the age of 5 years
• Complicated by wheelchair dependency, cardiomyopathy, and mild developmental delay

Question 10

What causes Duchenne muscular dystrophy?

Answer 10

• It is caused by pathogenic variants in DMD gene on chromosome Xp21.

The unmutated DMD gene :
-Encodes dystrophin protein
-But then, a mutation occurs. This leads to a deficiency of dystrophin protein.

-2/3 of cases are inherited (i.e. mother is a carrier)

Question 11

Why do we even see Duchenne muscular dystrophy cases in the population?

Answer 11

Coz of mothers or women who are carriers but never present with the disease. They be spreading it to kids, and males, and just to the population in general.

Question 12

We know females are least likely to be affected by X-linked recessive disoders. But in some cases they do get this. And what is the explaination to this?

Answer 12

• Homozygosity for XLR disorders
• Skewed X-inactivation
• Numerical X chromosome abnormalities
• X-autosome translocations