19.03.02 X-linked dominant and lethal

Question 1

X linked dominant (XLD) inheritance

Answer 1

• Expressed by HET females and HEMI males
• Both sexes affected, but more females than males, although males tend to be more severe
• Affected female - 50% of having an affected child
• Affected male - all daughters are affected, all sons are unaffected
• Can be confused to AD inheritance, but key is to look at children of affected males. All sons will be healthy and all daughters unhealthy if XLD

Question 2

Example of XLD - X-linked Alport syndrome

Answer 2

• Most common form of Alport syndrome
• Kidney disease (often end stage), blood and protein found in urine, sensorineural hearing loss, eye abnormalities
• Caused by mutation in COL4A5 (Xq22.3)

Question 3

Example of XLD - FRAX

Answer 3

• Inherited ID disorder
• Affect females and males, but males tend to be more severe
• CGG expansion in FMR1 gene

Question 4

XLD with male lethality

Answer 4

• Dominant mutation on X mutation only seen in females
• Affected males are very rare because its lethal (exception would be XXY males)
• Often see recurrent miscarriage (male pregnancies)
• Get skewed sex ratio - if mother is affect then often see an even split between unaffected female, affected female, and unaffected male.

Question 5

Example of XLD lethal - Incontinentia pigmenti

Answer 5

• Affects skin, nails, teeth, hair, eyes
• only 7% are males (and tend to be XXY or mosaic)
• Mutation in NEMO (Xq28) - common deletion of exons 4-10 found in 80% of patients

Question 6

Example of XLD lethal - Rett syndrome

Answer 6

• Normal development during first 6-18 months, then stagnation and then rapid regression in language and motor skills. Also get repetitive, stereotypical hand movements
• Mutation in MECP2 - get 8 common C>T missense and nonsense mutations in exons 3 and 4 (60% of all variants)
• Some males can be born but are very severe and normally die young (exceptions are XXY and post zygotic somatic mosaicism)

Question 7

X linked disorders in females

Answer 7

• very variable phenotypes in females normally due to skewed X inactivation
• Can be very mild (skewing favours inactivation of mutated allele) or very severe (favouring inactivation of normal allele, so appear more like a male)

Question 8

XLD - males can also be unaffected

Answer 8

• Some conditions where males are inaffected or very mild, and HET females are much more severe
• e.g. Craniofrontonasal syndrome (CFNS) - HET females express WT and KO alleles so get two cell populations. (mosaic) These interfere with each other and affect the expression of EFNB1 gene, thereby affecting cell migration.
• Males only have the KO cell population so don’t get this interference

Question 9

Pseudoautosomal region

Answer 9

• PAR are located on end of X chromosome (they are identical on X and Y)
• Genes in these regions don’t go through X inactivation
• They are either AD or AR and don’t act like X-linked genes