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Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease.
Luzón-Toro, Berta; Gui, Hongsheng; Ruiz-Ferrer, Macarena; Sze-Man Tang, Clara; Fernández, Raquel M; Sham, Pak-Chung; Torroglosa, Ana; Kwong-Hang Tam, Paul; Espino-Paisán, Laura; Cherny, Stacey S; Bleda, Marta; Enguix-Riego, María Del Valle; Dopazo, Joaquín; Antiñolo, Guillermo; García-Barceló, María-Mercé; Borrego, Salud.
Afiliación
  • Luzón-Toro B; Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
  • Gui H; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
  • Ruiz-Ferrer M; Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Sze-Man Tang C; Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Fernández RM; Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
  • Sham PC; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
  • Torroglosa A; Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Kwong-Hang Tam P; Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Espino-Paisán L; Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
  • Cherny SS; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
  • Bleda M; Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Enguix-Riego Mdel V; Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Dopazo J; State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Antiñolo G; Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • García-Barceló MM; Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
  • Borrego S; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
Sci Rep ; 5: 16473, 2015 Nov 12.
Article en En | MEDLINE | ID: mdl-26559152
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.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Heterogeneidad Genética / Secuenciación de Nucleótidos de Alto Rendimiento / Exoma / Enfermedad de Hirschsprung Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Female / Humans / Male Idioma: En Revista: Sci Rep Año: 2015 Tipo del documento: Article País de afiliación: España

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Heterogeneidad Genética / Secuenciación de Nucleótidos de Alto Rendimiento / Exoma / Enfermedad de Hirschsprung Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Female / Humans / Male Idioma: En Revista: Sci Rep Año: 2015 Tipo del documento: Article País de afiliación: España