Segregation at three loci explains familial and population risk in Hirschsprung disease

Abstract

Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.The molecular dissection of 'model' disorders is crucial to the elucidation of complex patterns of inheritance, which have been difficult to assess by other means 1-3 . HSCR is a neurocristopathy characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the gastrointestinal tract 4 . The phenotype usually occurs in isolation and is classified by extent of aganglionosis into long-segment (L-HSCR, 20% of affected individuals) and short-segment (S-HSCR, 80%) forms, each with distinct genetic characteristics 5 . HSCR is hereditary but nonmendelian with risk varying by gender, segment length and co-occurrence of non-enteric phenotypes 6 . We have previously concluded that RET is the major gene involved in HSCR, for several reasons: (i) only one affected family unlinked to RET has been reported 7 ; (ii) coding sequence mutations occur in 50% of familial and 15−35% of sporadic cases 8 ; (iii) even when the major mutation is in EDNRB, RET variants make some contribution to susceptibility 9 and (iv) homozygous Ret-null mice have full sex-independent penetrance of aganglinonosis 10 . Yet, RET mutations may not be sufficient to lead to aganglionosis, as the penetrance of mutant alleles is 65% in males and 45% in females 8 . RET is the major gene underlying HSCR primarily in families enriched for L-HSCR 5 . The genes critical for the complex inheritance of the much more common S-HSCR remain unknown.We carried out a genome search of the number and locations of genes conferring susceptibility to S-HSCR in 49 affected families ascertained through a proband with S-HSCR, using 371 tandem repeat polymorphisms at a map resolution of approximately 10 cM. With an incidence of 1 in 6,250 livebirths and a sibling recurrence risk of 3% (ref. 5), the risk ratio (λ) for S-HSCR is 187.5, which allowed us to identify the major segregating risk factors 6 . Consequently, we could both impute or refute the role of all known candidate genes (see Methods), independently assess the role of RET and identify new genes invol...

Cys611Ser mutation in RET proto-oncogene in a kindred with medullary thyroid carcinoma and Hirschsprung's disease

“…39 -47 Furthermore, some other loci were proposed to be associated with the risk of HSCR. 48 Although the possibility that the mutations of these genes are present and affect the development of HSCR in this case is not excluded, it is not practical to screen all the genes. Among the genes described above, the RET status is the most important for follow-up of HSCR patients because the patients who have a mutation at codon 609, 611, 618, or 620 in the RET gene are at risk for the development of MTC.…”

Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

“…Families from the US and Spanish data set have already been published. 2,11,12 Because parental DNA was not available for all RET CDS mutation carriers patients, parental origin of RET CDS mutations was only searched for in 18 affected sib-pairs and 36 sporadic cases. A total of 15 de novo mutations were detected for sporadic cases.…”

“…A small subgroup of patients present a rare coding sequence mutation (CDS) of the RET gene with a high and sex-dependent penetrance. 1,2 The remaining group of patients have a risk allele for a noncoding polymorphism in an enhancer element of IVS1, rs2435357, with a low and sex-dependent penetrance [3][4][5][6] (found in 90% of the patient alleles versus 19.4% in the 1000 genomes project). The subgroup with RET CDS mutations represents B45% of familial cases and 7-20% of sporadic cases.…”

Presumptive pre‐sertoli cells express genes involved in cell proliferation and cell signalling during a critical window in early testis differentiation

“…In humans, haploinsufficiency of SOX10 can result in Hirschprung disease defined by an absence of enteric ganglia in the myenteric and submucosal plexus along variable lengths of the distal gut (Gabriel et al, 2002). In homozygous Sox10 knockout mice, melanocytes, peripheral glia and the enteric nervous system are missing (Kellerer et al, 2006).…”