2. X -linked dominant and lethal

Question 1

Describe the features of X-linked dominant inheritance

Answer 1

Expressed in het females and hemi males

Affected female has 50% chance of having affected child

Affected male has 100% chance of having affected daughter, sons not affected

Question 2

Give 2 examples of an X-linked dominant disorder

Answer 2

1. X-linked Alport syndrome
2. Rett syndrome

Question 3

What causes Alport syndrome & what is the phenotype?

Answer 3

X-linked Alport syndrome - COL4A5

Kidney disease, haematuria, protein in urine, hearing loss, eye abnormalities

Almost exclusively in females, lethal in males (except Kilnefelters)

Question 4

What causes Rett syndrome & what’s the inheritance?

Answer 4

MECP2

Low recurrence - mostly de novo, occasionally germline mosaic

Question 5

What is the clinical phenotype of Rett syndrome?

Answer 5

Normal development until 18 months, then rapid regression in motor/language skills. Variable phenotype in females

Males have severe neonatal encephalopathy

Question 6

Give an example of an XLD disorder where males are unaffected, plus background info

Why are females affected?

Answer 6

Craniofrontonasal syndrome

Premature closure of certain bones of the skull

EFNB1

Random X-inactivation –> Mosaic expression pattern. Cellular interference between WT and mutant cell populations

Question 7

What can influence the severity of disease in XLD disorders in females?

Answer 7

Skewed X-inactivation

Can also result in het females manifesting XLR disease usually seen only in males