X-linked inheritance

Question 1

Define X inactivation and describe its molecular basis and clinical relevance

Answer 1

• occurs early in development where one X remains active while others become permanently inactive
• Initial X inactivation decision is random, the effects are permanent in its somatic descendants of each cell
• Inactive X chromosomes remain highly condensed

-Clinical relevance=>skewed X inactivation causes ratio to be uneven which can lead to mild phenotypic consequences if a female is heterozygous for an X-linked mutation

Question 2

Define X inactivation regarding its molecular basis

Answer 2

-Molecular=> additional modification with DNA methylation and histone modification

Question 3

Define X inactivation regarding its clinical relevance

Answer 3

-Clinical relevance=>skewed X inactivation causes ratio to be uneven which can lead to mild phenotypic consequences if a female is heterozygous for an X-linked mutation

Question 4

Define X linked inheritance and be able to track X linked traits in pedigrees including obligate carrier status.

Answer 4

predominantly, males are affected due to X hemizygosity so typical pattern is affected males through the maternal lineage where the females are generally just carriers
no father to son transmission

Question 5

T/F In males that are XY, they are hemizygous for essentially all genes on the X chromosome

Answer 5

True

X^A, Y; X^a,Y

Question 6

T/F Females can be either homozygous or heterozygous for genes on the X chomosome

Answer 6

true

Question 7

In regards to the Y chromosome, it has a limited number of genes on the region of the chromosome that is referred to as what?

Answer 7

-pseudoautosomal region

Question 8

What determines the male sex?

Answer 8

-SRY gene and male fertility

Question 9

Describe the pseudoautosomal region of the Y chromosome

Answer 9

• short regions of homology on Xp and Yp (also Xq & Yq)
• Promotes sex chromosome pairing in prophase I of male meiosis

Question 10

What is the only non-homologous chromosome pair?

Answer 10

XY chromosomes

Question 11

Describe the number of X linked genes in females vs males

Answer 11

-2 copies in females vs 1 copy in males

Question 12

In females, the expression of X linked genes is reduced to match what and through what mechanism?

Answer 12

-match male levels through X activation

Question 13

T/F X inactivation can be reversed in somatic descendents

Answer 13

-False, it is permanent

Question 14

Normal females are X chromosome mosaics. What does this mean in regards to their cells?

Answer 14

-Express the paternally derived X in half their cells and the maternally derived X in the other half

Question 15

What gene is a regulator of X inactivation?

Answer 15

-XIST gene (X-inactivation specific transcript)

Question 16

Describe the XIST gene

Answer 16

• produces a non-coding RNA that coats and marks the inactive chromosome
• expressed ONLY from the INACTIVE X chromosome
• mature RNA product “coats” the chromosome, “marking” it as inactive

Question 17

How does the inactivated X chromosome maintain the inactive state?

Answer 17

-additional modification with DNA methylation and histone modification

Question 18

Describe the complexity of the X inactivation in regard to regulators of the XIST gene

Answer 18

-complex with upstream and downstream regulators of XIST gene to achieve both initiation and maintenance of inactivation

Question 19

Does the X inactivation occur in an even pattern on the chromosome?

Answer 19

• *-No, it is uneven along the length of the X chromosome with some genes escaping X inactivation altogether which is bi-allelic expression
• 15-20% of X linked genes are NOT inactivated but mostly on Xp**

Question 20

Where do the genes generally escape the inactivation?

Answer 20

pseudoautosomal region

Question 21

What process achieves the dosage compensation?

Answer 21

-epigenetic process

Question 22

What is the only time when the X inactivation can be reversed?

Answer 22

-female germline just prior to meiosis

Question 23

Recognize a punnett square for females regarding X linked recessive inheritance

Answer 23

X2 is a mutation

Question 24

Recognize a punnett square for males regarding X linked recessive inheritance

Answer 24

Question 25

Regarding X linked recessive inheritance, describe the relationship to the offspring to sons and daughters if the female is the carrier

Answer 25

• half their sons will be affected
• Half daughters will be carriers

Question 26

Regarding X linked recessive inheritance, describe the relationship to the offspring to sons and daughters if the male is affected

Answer 26

• All daughters will be obligate carriers if able to reproduce
• No disease risk to sons

Question 27

What are 4 principles of X-linked inheritance that will inform risk to potential parents toward their offspring?

Answer 27

family history evaluates carrier risk and recurrence risk

multiple affected family members are consistent with a familial mutation

single affected family member (new mutation or inherited mutation)

Affected females are observed rarely

Question 28

How can you determine if a woman is an obligate carrier of an X linked recessive disease?

Answer 28

woman with 2 or more affected sons

woman with an affected brother and affected son

Question 29

Why are affected females rarely observed?

Answer 29

-mildly affected heterozygote due to skewed X inactivation but could only be seen in a daughter of an affected male and female carrier

Question 30

Why can X-linked inheritance patterns whether dominant or recessive be ambiguous?

Answer 30

X inactivation, reduced viability and variable expression

Question 31

What is the primary mode of transmission of X-linked traits?

Answer 31

• primarily affect males due to hemizygous but done through carrier females
• cannot occur through male-to-male transmission