Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease

Abstract

Hirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR.

Common genetic variants in GAL, GAP43 and NRSN1 and interaction networks confer susceptibility to Hirschsprung disease

“…Taking advantage of whole exome sequencing, several genes, including DENND3, FAT3 and AGL, were linked to HSCR pathogenesis. [9][10][11] NRG3 has recently been proved to be a new HSCR risk gene based on exome sequencing and genomewide copy number analysis, 2,12 which was further confirmed by our previous work. 13 In addition, genomewide association studies on HSCR trios and sporadic cases have uncovered the class 3 semaphorin gene cluster and certain large-scale chromosomal aberrations regarding HSCR aetiology.…”

Sporadic Hirschsprung Disease: Mutational Spectrum and Novel Candidate Genes Revealed by Next-generation Sequencing

“…Familial occurrence, male predominance, high sibling recurrence risk, and the pattern of associated malformations strongly imply a genetic etiology 2 , 17 . However, non-mendelian inheritance in human and mouse model studies suggest the presence of significant genetic heterogeneity and multifactorial causes of the disease 18 – 20 . Mutations in >15 genes are known to be associated with HSCR.…”

Whole-genome analysis of noncoding genetic variations identifies multigranular regulatory element perturbations associated with Hirschsprung disease

“…When exploring the functions of the 552 genes, an expanded gene set was created by first adding 26 known HSCR genes, including BACE2, DNMT3B, ECE1, EDN3, EDNRB, FAT3, GDNF, GFRA1, KIAA1279, L1CAM, NRG1, NRG3, NRTN, NTF3, NTRK3, PHOX2B, PROK1, PROKR1, PROKR2, PSPN, SEMA3A/C/D, SOX10, TCF4, and ZFHX1B [8][9][10][11][12][13] . After that, genes involved in ENS function or NC migration that had Reactome functional interactions with at least one gene already in the expanded gene set were further added to it, including CDC42 61 , CUL1 47 , ERBB2/3/4 61 , GNAI1 104 , GRB2 105,106 , NRP1/2 61 , PAX3 71,107 , PLXNB1 108 , ROBO1/2/3 61 , SLIT1/2/3 61 , and TCF12 107 .…”