title: 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.
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Luzón-Toro
authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Gui
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Macarena
authors.initials: M
authors.lastname: Ruiz-Ferrer
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Clara
authors.initials: C
authors.lastname: Sze-Man Tang
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Fernández
authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Torroglosa
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Paul
authors.initials: P
authors.lastname: Kwong-Hang Tam
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Espino-Paisán
authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.|Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Bleda
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: María Del Valle
authors.initials: Mdel V
authors.lastname: Enguix-Riego
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.|Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.|Functional Genomics Node, (INB) at CIPF, Valencia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: María-Mercé
authors.initials: MM
authors.lastname: García-Barceló
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
mesh_terms: D000483:Alleles; D015820:Cadherins / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics; D059472:Exome; D005190:Family; D005260:Female; D018740:Genetic Heterogeneity; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006627:Hirschsprung Disease / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D015820:Cadherins; C448779:FAT3 protein, human; D004815:Epidermal Growth Factor