PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.
The Phox2b gene is necessary for autonomic nervous-system development. Phox2b-/- mice die in utero with absent autonomic nervous system circuits, since autonomic nervous system neurons either fail to form or degenerate. We first identified the Phox2b human ortholog, PHOX2B, as the gene underlying congenital central hypoventilation syndrome (CCHS, or Ondine curse), with an autosomal dominant mode of inheritance and de novo mutation at the first generation. We have subsequently shown that heterozygous mutations of PHOX2B may account for several combined or isolated disorders of autonomic nervous-system development--namely, tumors of the sympathetic nervous system (TSNS), such as neuroblastoma and late-onset central hypoventilation syndrome. Here, we report the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease and/or TSNS. The mutation-detection rate was 92.6% (174/188) in our series, and the most prevalent mutation was an in-frame duplication leading to an expansion of +5 to +13 alanines in the 20-alanine stretch at the carboxy terminal of the protein. Such findings suggest PHOX2B mutation screening as a simple and reliable tool for the diagnosis of CCHS, independent of the clinically variable phenotype. In addition, somatic mosaicism was detected in 4.5% of parents. Most interestingly, analysis of genotype-phenotype interactions strongly supports the contention that patients with CCHS who develop malignant TSNS will harbor either a missense or a frameshift heterozygous mutation of the PHOX2B gene. These data further highlight the link between congenital malformations and tumor predisposition when a master gene in development is mutated.
Trochet
Delphine
D
Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
O'Brien
Louise M
LM
Gozal
David
D
Trang
Ha
H
Nordenskjöld
Agneta
A
Laudier
Béatrice
B
Svensson
Pär-Johan
PJ
Uhrig
Sabine
S
Cole
Trevor
T
Niemann
Stephan
S
Munnich
Arnold
A
Gaultier
Claude
C
Lyonnet
Stanislas
S
Amiel
Jeanne
J
D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000150:complications / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006579:Heterozygote; D006627:Hirschsprung Disease / Q000150:complications / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D009030:Mosaicism; D020125:Mutation, Missense; D009423:Nervous System Neoplasms / Q000150:complications / Q000235:genetics*; D011247:Pregnancy; D012307:Risk Factors; D020182:Sleep Apnea, Central / Q000150:complications / Q000151:congenital* / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors