Genetic profile of a multiplex Hirschsprung disease family

Abstract

Hirschsprung disease (HSCR), also known as congenital megacolon, is characterized by the absence of enteric ganglia in the hindgut. HSCR is a rare multigenic neurocristopathy with receptor tyrosine kinase, RET, being the major HSCR gene. Increasing evidence from genetic studies suggests that a sensitized genetic background of reduced RET expression conferred by the regulatory HSCR-associated common variant is critical for the phenotypic expression of HSCR. We performed a whole-genome sequencing study of a multiplex HSCR family with two affected siblings, one with more severe long-segment HSCR (LHSCR) while another with the common form of short-segment HSCR (SHSCR). A truncating de novo mutation of KIF26A was identified in the LHSCR patient where knockout of kif26a in mice was shown to present with hyperganglionosis and megacolon. We hypothesized that KIF26A de novo mutation acts as a genetic modifier contributing to the increased severity and there exists other causal variants or genetic modifiers shared between the affected siblings for the phenotypic expression. Combined with the approach of polygenic risk score, we delineated the relationship between the sensitized genetic background of common variants and constellations of rare DNA changes, including copy number variations, with respect to risk of HSCR. Latest results of the genetic profile of the family will be presented.