Anna Löf Granström1, Ellen Markljung2, Katharina Fink3, Edvard Nordenskjöld2, Daniel Nilsson4, Tomas Wester5, Agneta Nordenskjöld1. 1. Division for Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska, University Hospital, Stockholm, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. 2. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. 3. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurology Huddinge, Karolinska University Hospital, Stockholm, Sweden. 4. Science for Life Laboratory, Department of Cell and Molecular Biology, Karolinska, Institutet, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 5. Division for Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska, University Hospital, Stockholm, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. Electronic address: tomas.wester@karolinska.se.
Abstract
PURPOSE: We identified a girl with Hirschsprung's disease (HSCR) whose mother and grandmother had HSCR associated with multiple sclerosis (MS). The aim of this study was to outline mutations in HSCR-related genes and MS susceptibility alleles in these three individuals. METHODS: The phenotypes were reviewed based on medical records. The three subjects had rectosigmoid HSCR verified with histopathology. The mother and grandmother fulfilled the McDonald criteria for MS. DNA was isolated from EDTA-preserved blood according to standard procedures. Exome sequencing aiming mainly at analyzing HSCR associated genes as well as Sanger sequencing for confirmation was performed. RESULTS: All affected individuals carry a novel heterozygous nonsense mutation in the EDNRB gene (c.C397T,p.R133X,refNM_000115), changing an arginine at position 133 into a premature stop codon. None of the subjects were homozygous for the HLA risk alleles for MS. CONCLUSION: We report a novel non-sense EDNRB gene mutation in a girl with HSCR and her mother and grandmother with HSCR and MS. We propose that this EDNRB gene mutation plays a role in the etiology of HSCR and also makes the subjects susceptible to MS.
PURPOSE: We identified a girl with Hirschsprung's disease (HSCR) whose mother and grandmother had HSCR associated with multiple sclerosis (MS). The aim of this study was to outline mutations in HSCR-related genes and MS susceptibility alleles in these three individuals. METHODS: The phenotypes were reviewed based on medical records. The three subjects had rectosigmoid HSCR verified with histopathology. The mother and grandmother fulfilled the McDonald criteria for MS. DNA was isolated from EDTA-preserved blood according to standard procedures. Exome sequencing aiming mainly at analyzing HSCR associated genes as well as Sanger sequencing for confirmation was performed. RESULTS: All affected individuals carry a novel heterozygous nonsense mutation in the EDNRB gene (c.C397T,p.R133X,refNM_000115), changing an arginine at position 133 into a premature stop codon. None of the subjects were homozygous for the HLA risk alleles for MS. CONCLUSION: We report a novel non-sense EDNRB gene mutation in a girl with HSCR and her mother and grandmother with HSCR and MS. We propose that this EDNRB gene mutation plays a role in the etiology of HSCR and also makes the subjects susceptible to MS.