POSTER NO: 418

PHOX2B gene is associated with Hirschsprung's disease

¹M.M. Garcia-Barceló, ²M.H. Sham, ¹V.C.H. Lui, ¹B.L.S. Chen, ³J. Ott, ¹P.K.H. Tam
¹Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong SAR, China, ²Department of Biochemistry, University of Hong Kong., Hong Kong SAR, China, ³Laboratory of Statistical Genetics, Rockefeller University, New York, USA

Hirschsprung's disease (HSCR, aganglionic megacolon) is a congenital malformation regarded as a multigenic neurocristopathy. The PHOX2B gene (paired mesoderm homeobox 2b) encodes for a transcription factor that coordinates neurogenesis. In mice, the homozygous disruption of the Phox2b results in HSCR-like phenotype. Furthermore, Phox2b regulates the expression of Ret, a gene that is highly relevant to HSCR. We explore the human PHOX2B gene as a potential HSCR susceptibility gene. Using PCR amplification and direct sequencing, 91 HSCR patients and 39 ethnically matched controls, were screened for PHOX2B coding regions as well as intron/exon boundaries for mutations and polymorphisms. Two novel polymorphisms (A/G2250; A/C3493) and one deletion (15 bp DEL3495) were identified. Case-control association studies revealed statistical significant differences for A/G2250 located in the intronic boundary region. Genotypes comprising allele G were underrepresented in the patient group (19% vs 38%; Chi square = 8.28; p = 0.015) and in males (19% vs 44%; Chi square = 8.71; p = 0.012) compared with male controls. This study provides further evidence of a multigenic aetiology for HSCR. The association of PHOX2B A/G2250 polymorphism with HSCR may represent a protective effect against HSCR phenotype in male or provide a linkage marker for other HSCR susceptibility gene loci.