Interaction between a chromosome 10 RET enhancer and chromosome 21 in the Down syndrome–Hirschsprung disease association

✍ Scribed by Stacey Arnold; Anna Pelet; Jeanne Amiel; Salud Borrego; Robert Hofstra; Paul Tam; Isabella Ceccherini; Stanislas Lyonnet; Stephanie Sherman; Aravinda Chakravarti

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 274 KB
• Volume: 30
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.20944

✦ Synopsis

Individuals with Down syndrome (DS) display a 40-fold greater risk of Hirschsprung disease (HSCR) than the general population of newborns implicating chromosome 21 in HSCR etiology. Here we demonstrate that the RET enhancer polymorphism RET 19.7 (rs2435357:C4T) at chromosome 10q11.2 is associated with HSCR in DS individuals both by transmission disequilibrium (P 5 0.0015) and case-control (P 5 0.0115) analysis of matched cases. Interestingly, the RET19.7 T allele frequency is significantly different between individuals with DS alone (0.2670.04), HSCR alone (0.6170.04), and those with HSCR and DS (0.4170.04), demonstrating an association and interaction between RET and chromosome 21 gene dosage. This is the first report of a genetic interaction between a common functional variant (rs2435357) and a not infrequent copy number error (chromosome 21 dosage) in two human developmental disorders.