X Linked Inheritance

Question 1

What is lyonization? How does it occur?

Answer 1

X-inactivation, occurs in females early in development and completely randomly, forming Barr bodies. On average, the X that’s inactivated is 50/50 maternal:paternal

Question 2

What gene regulates the inactivation process? Which X chromosome is it expressed in?

Answer 2

XIST - inactive X specific transcripts gene. Only gene other than the pseudoautosomal region on the inactivated X chromosome which is expressed

Question 3

How does XIST work?

Answer 3

Encodes non-coding mRNA which transcriptionally silence the X chromosome via binding repressor proteins

Question 4

How is the information about the Barr-bodied chromosome carried in subsequent cell divisions?

Answer 4

Via DNA methylation

Question 5

In women with X-chromosome deletions, which X is inactivated and what is the exception to this?

Answer 5

The X-chromosome with the deletion is inactivated

Exception: X:autosome translocation, which inactivates the normal X chromosome in order to prevent functional monosome of the autosome

Question 6

What is the significance of the pseudoautosomal region of the X chromosome?

Answer 6

Not inactivated in the Barr body, it’s the part which pairs in metaphase with the Y chromosome via homologous pairing. It is called “pseudoautosomal” because it is always activated, like an autosome’s.

Question 7

What is the hallmark of X-linked inheritance?

Answer 7

No male to male transmission

Question 8

What is the general normal process of hemostasis (clotting)? What protein activates platelets, and what protein forms the mesh?

Answer 8

1. Vascular constriction to limit blood flow
2. Platelet activation via thrombin, aggregate at site of injury forming a plug
3. Formation of mesh via fibrin, which entraps the plug
4. Dissolution of clot to allow normal blood flow

Question 9

What are the most important clinical features of hemophilia A/B? What percentage will have a family history?

Answer 9

Defective clotting cascade

1. Joint + muscle hemorrhages
2. Easy bruising / prolonged bleeding
3. Common hematomas in muscles or intracranial bleeding
4. Hemarthroses - bleeding in the joints which can lead to arthritis

50% of both will have a family history

Question 10

What causes Hemophilia A? What is its penetrance?

Answer 10

Absence of factor 8 (VIII), which is needed for 9a’s conversion of 10 to 10a. 100% penetrant in males, 10% in females (just some easy bruising)

Question 11

What type of mutation is Hemophilia A?

Answer 11

About 50% of people have the same intronic inversion, a very common type of mutation. Causes three exons to change order within the gene due to homolgous crossing over.

Question 12

What causes Hemophilia B? What is the relative prevalence?

Answer 12

Deficiency in Clotting Factor 9 (christmas factor)

much less prevalent than Hemophilia A. There’s a large amount of variation in the mutation

Question 13

What are the primary treatments for Hemophilia A?

Answer 13

1. Desmopressin, which releases unused factor 8 from cells

2. IV factor 8, which used to be given in unpurified plasma

Question 14

What are the features of Duchenne muscular dystrophy?

Answer 14

X-linked recessive disorder caused by deterioration of muscle cells, especially proximal first. Can cause cardiomyopathy and skeletal deformities secondary to weakness. Onset is in early childhood, with death by 3rd decade due to cardiac or respiratory complications

Question 15

What are the clinical signs of DMD?

Answer 15

1. Elevated creatine kinase (10x in DMD, 5x in BMD)
2. Gower manuever -
3. Pseudohypertrophy of calves - due to destruction / inflammation

Question 16

What is the Gower manuever?

Answer 16

The patient will start lying prone, then walk up their body to assume an upright posture due to proximal muscle weakness.

Question 17

What is Becker muscular dystrophy (BMD)?

Answer 17

Also X-linked, but milder than Duchenne. Rarer than DMD, but has a later onset allowing for a longer lifespan

Question 18

What causes DMD / BMD? What determines outcome

Answer 18

Mutations of dystropin gene, which is the largest known gene. Most are deletions, and about 1/3 are novel. The precise nature of the mutation determines the severity. 60-70% of cases will be caused by deletions in 1 or more exon.

Dystrophin structurally links myofibrillar membrane to contractile proteins

Question 19

What other tests can be run to diagnose DMD / BMD?

Answer 19

EMG, muscle biopsy (in the past), immunohistochemistry, and molecular testing (Standard of care now)

Question 20

Different alleles of what gene can cause androgen insensitivity syndrome / spinal and bulbar muscular atrophy? What is this called?

Answer 20

Androgen receptor gene,

this is a strange form of allelic heterogeneity, since different mutations in the same gene can cause different diseases

Question 21

What ultimately leads to testicular feminization in androgen insensitivity syndrome?

Answer 21

End-organ unresponsiveness causes excess testosterone to be converted to estriol and subsequent feminization (breast development, blind vagina, absent / sparse pubic or axillary hair)

Question 22

What are the clinical features of androgen insensitivity syndrome?

Answer 22

Karyotype 46,XY
Normal appearing tall, thin females
Primary amenorrhea
Normal female external genitalia
Absent uterus / fallopian tubesm with bilateral internal testes increasing risk of gonadoblastoma

Question 23

Why do Androgen insensitive patient develop testes in the first place?

Answer 23

Gonadal differentiate is determined by presence of SRY genes, by androgens are required for development of male external genitalia

Question 24

What is the mutation in androgen insensitivity syndrome?

Answer 24

Premature termination of protein

Question 25

What is the mutation in spinal and bulbar muscular atrophy and what is this syndrome also called?

Answer 25

Kennedy’s disease
Mutation is trinucleotide repeat (CAG) which alters protein conformation, causing a gain of function mutation which expands the receptor with a polyglutamine stretch

Question 26

Why are women not affected by Kennedy’s disease?

Answer 26

There aren’t high enough circulating androgens to activate mutant receptor, even in homozygous recessive

Question 27

What are the clinical features of Kennedy’s disease?

Answer 27

Difficulty walking (proximal muscle wakness)
Difficulties speaking / swallowing (aspiration) due to bulbar atrophy
Gynecomastia, testicular atrophy, and reduced fertility due to mild androgen insensitivity

Question 28

What are the hallmarks of X-linked dominant inheritance?

Answer 28

Conditions affect both males and females, with no male-male transmission. However, males typically have a more severe phenotype (no wild type X to help)

Question 29

What is the most common inherited cause of intellectual disability in males?

Answer 29

Fragile X syndrome - moderate to severe

Question 30

What are the physical features of Fragile X?

Answer 30

Prominent, square jaw, macroorchidism (large testes), intellectual disability, macrocephaly, behavioral problems

Question 31

Who is most affected by fragile X?

Answer 31

Males, although females have half the prevalence since it is X-linked dominant

Question 32

What causes fragile X syndrome? When is someone at risk?

Answer 32

> 200 trinucleotide repeats CGG in the FMR1 gene. This will cause stopping of translation (intronic region).

> 55 repeats is considered “premutation”, and there is repeat instability when this is maternally transmitted.

Question 33

What are two conditions associated with the pre-mutation state of Fragile X?

Answer 33

1. Fragile X Tremor Ataxia Syndrome (FXTAS) - late onset, progressive cerebellar ataxia which affects males more
2. Premature Ovarian Insufficiency (POI) - cessation of menses in 20% of premutation carriers due to excess mRNA

Question 34

What is meant by “anticipation” in genetics?

Answer 34

Apparent worsening of a disorder in each generation, as explained by trinucleotide repeat syndromes

Question 35

What important genes are Y-linked?

Answer 35

SRY - sex-determining region of Y, can sometimes translocate to X

Azoospermia factor regions, including deleted in azoospermia (DAZ) gene

RNA-binding proteins essential for spermatogenesis