Molecular basis of congenital central hypoventilation syndrome : PHOX2B mutation and its haplotypes

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With congenital central hypoventilation syndrome (CCHS), most patients carry de novo polyalanine expansion mutation in PHOX2B. We reported previously that de novo polyalanine expansion mutations were of paternal origin and derived from unequal sister chromatid exchange during spermatogenesis. In the present study, we analyzed the relation between the haplotypes and de novo polyalanine expansion in PHOX2B and confirmed the origin and expanded mechanism of de novo polyalanine expansion mutation. We also found that haplotypes carrying rs17884724 : A>C were detected frequently in seven-alanine expanded (27 alanine) mutant alleles, most prevalent mutations in CCHS. The allele with rs17884724 : A>C would make fewer nucleotide mismatches in the misalignment at crossing over than the allele without rs17884724 : A>C. High frequency ofrs17884724 : A>C in seven-alanine expansion mutations would also support the unequal crossover mechanism for polyalanine expansion.More than 90% of the alanine expansion mutations had been considered to be de novo mutation, 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 10 patients (22%) inherited alanine expansion mutation from a parent with late-onset central hypoventilation syndrome or asymptomatic parents with somatic mosaicism. Genetic analysis is needed for definite diagnosis and effective genetic counseling.