Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome.

ABSTRACT

Congenital central hypoventilation syndrome (CCHS; MIM 209880) is caused mostly by dominant alanine expansion (most prevalent is 7-alanine expansion) mutations in PHOX2B. More than 90% of the alanine expansion mutations had been considered to be de novo due to unequal crossover during gametogenesis. However, a recent report stated that 25% of patients inherited the alanine-expanded allele from their parents with somatic mosaicism or constitutive mutation. We studied inheritance in 45 unrelated families, and found that one patient (2%) inherited 5-alanine expansion mutation from a parent with late-onset central hypoventilation syndrome and nine patients (20%) inherited 5- to 7-alanine expansion mutation from apparently asymptomatic parents with somatic mosaicism. Analysis using a sensitive method would be recommended to all parents of CCHS proband due to high incidence of somatic mosaicism. The absence of an alanine-contracted allele (expected counterpart allele in unequal crossover) and the highest prevalence of 6-alanine expansion mutation in somatic mosaicism suggest that the somatic mosaicism is likely caused by a mechanism other than an unequal crossover, such as a replication mechanism.