18.03.02 X-linked dominant and lethal Flashcards Preview

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Flashcards in 18.03.02 X-linked dominant and lethal Deck (17):

What are some pedigree indicators a disorder may be XLD, rather than AD?

Affected males have no affected sons.
Excess of affected heterozygous females


What are some pedigree indicators a disorder is XLD with male lethality?

H/o miscarriage (50% of males affected)
Skewed sex ratio of liveborns


Give two examples of disease which can be considered to be X-linked dominant.

1. X-linked hypophosphatemia (PHEX mutations)
2. X-linked Alport syndrome (COL4A5 mutations)
3. Fragile X (debatable) (FMR1 mutations)


What is the prevalence and phenotype of X-linked hypophosphatemia?

1 in 20,000. Rickets with bone deformities, dental anomalies, low serum phosphate, short stature.


What is the genetic cause of X-linked hypophosphatemia?

PHEX (Xp22.1) protein stimulates production of FGFR3 in bone. PHEX mutations cause the overactivity of FGFR3 or reduce its normal breakdown pathway.
FGFR3 presence inhibits phosphate absorption by the kidneys - phosphate is excreted and not available in the bloodstream for normal bone formation and maintenance.


What is the prevalence and phenotype of X-linked Alport syndrome?

1 in 50,000. Disorder of collagen function manifesting in abnormal kidney function - haematuria and proteinuria ultimately leading to end-stage renal failure/disease in the majority of cases requiring dialysis or transplant. Patients may also have sensorineural hearing loss and ocular abnormalities.


Give examples of disease with a X-linked dominant with male lethality inheritance pattern.

Intercontinentia pigmentia
Rett syndrome
Oral-facial-digital syndrome type 1


What is the phenotype of intercontinentia pigmentia?

Nail dystrophy (40%), dental abnormalities (80%), eye abnormalities (30%). Four stage skin rash: blistering - wart-like rash- swirling macular hyperpigmentation - linear hypopigmentation (Blaschko's lines)


What is the genetic cause and disease mechanism of Intercontinentia pigmentia?

Mutation in IKBKG at Xq28. 80% have exon 4-10 deletion. IKBKG regulates NF-kappa-B involved in cell-death mechanism. Unregulated NF-kappa-B = increased cell death in response to normal levels of stimuli.
High penetrance with variable expressivity.


What is the incidence and phenotype of Rett syndrome?

~1 in 10,000 female births
Normal development (6-18 months), developmental stagnation followed by regression. Stereotypical, repetitive hand movements. Can survive into adulthood but with a high incidence of sudden death. Variable phenotype ranging from apparently normal to severely affected


What is the genetic cause and mutation spectrum of Rett syndrome?

Mutations in MECP2, FOXGL and CDKL5.
MECP2 mutations account for 80% of cases. 8 missense/nonsense C>T mutations at CpGs in exons 3 and 4 account for 60% of MECP2 cases. 7/8 in exon 4.


Males with severe MECP2 mutations typically present with severe neonatal encephalopthy resulting in death before age 2, however there are cases of male Rett syndrome patients surviving to adulthood. What are the possible mechanisms for this?

1) 46,XY patients with mild MECP2 mutations e.g. p.(Ala140Thr) which results in some functional MECP2 protein and a moderate-severe ID phenotype in males (mild in females) (1.3-1.7% of mod-severe male ID)
2) 47,XXY
3) Somatic mosacisim


What is the incidence and phenoytpe of oral-facial-digital syndrome type 1?

1 in 50,000 to 1 in 250,000
Oral, facial, digital, brain and kidney abnormalities
50% ID


What is the genetic cause of OFD1?

Mutations in OFD1 at Xp22.2-3
75% sporadic mutation rate


If a mother is affected with a X-linked dominant disorder with male lethality what proportion of her offspring are expected to be affected?

1/3 affected daughters
(1/3 unaffected daughters, 1/3 unaffected sons)


What is the recurrence risk for a mutation negative unaffected mother of a child with a XLD with male lethality syndrome?

1% due to possibility of germline mosaicism and sporadic mutation


Give an example of a XLD condition in which females are more severely affected than males. Why is this?

Craniofrontonasal syndrome (CFNS) - females more severely affected due to cellular interference between wt and mutant cell populations.

CFNS caused by mutations in EFNB1 (Xq13.1) which encodes ephrin-B1. This is a transmembrane protein required for normal cell signalling to direct cell migration and pattern formation.
Males may be more severely affected if XXY or somatic mosaics.