PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome.
BACKGROUND
Late-onset central hypoventilation syndrome (LO-CHS) is a rare disorder that may manifest as early as infancy or as late as during adulthood. The potential overlap of LO-CHS with congenital CHS is under debate, even though both disorders can result from heterozygous PHOX2B gene mutations.


OBJECTIVE
To characterize the PHOX2B status in a series of 25 patients with LO-CHS referred from 3 months of age to adulthood. Whenever a PHOX2B mutation was identified, we ascertained its germline or somatic origin in both patients with LO-CHS and in 15 parents of probands with congenital CHS found to harbor a PHOX2B mutation.


METHODS
The PHOX2B gene was analyzed by direct DNA sequencing and origin of the mutation evaluated by fluorescent PCR.


RESULTS
We have identified a heterozygous PHOX2B gene mutation in 17 of 25 patients with LO-CHS. The far most frequent mutation results in a germline +5 alanine expansion in the series of 20 alanines (15 cases) that show incomplete penetrance and variable expressivity, possibly resulting from combined environmental and genetic factors. PHOX2B frameshift and missense mutations have also been identified in patients with LO-CHS. Importantly, one parent found to harbor a somatic mosaic for a +8 alanine expansion developed alveolar hypoventilation in his 40s.


CONCLUSIONS
These data indicate that PHOX2B gene mutations should be systematically examined in any adult with unexplained central hypoventilation and raise the question of follow-up for apparently healthy parents found to harbor a somatic mosaic for the PHOX2B mutation identified in their child.
Trochet
Delphine
D
Département de Génétique, Hôpital Necker-Enfants Malades 149, rue de Sèvres, 75743 Paris Cedex 15, France.
de Pontual
Loïc
L
Straus
Christian
C
Gozal
David
D
Trang
Ha
H
Landrieu
Pierre
P
Munnich
Arnold
A
Lyonnet
Stanislas
S
Gaultier
Claude
C
Amiel
Jeanne
J
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D042622:DNA Repeat Expansion; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D020125:Mutation, Missense; D020182:Sleep Apnea, Central / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors