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BackgroundCongenital multiple intestinal atresia (MIA) is a severe, fatal neonatal disorder, involving the occurrence of obstructions in the small and large intestines ultimately leading to organ failure. Surgical interventions are palliative but do not provide long-term survival. Severe immunodeficiency may be associated with the phenotype. A genetic basis for MIA is likely. We had previously ascertained a cohort of patients of French-Canadian origin, most of whom were deceased as infants or in utero. The goal of the study was to identify the molecular basis for the disease in the patients of this cohort.MethodsWe performed whole exome sequencing on samples from five patients of four families. Validation of mutations and familial segregation was performed using standard Sanger sequencing in these and three additional families with deceased cases. Exon skipping was assessed by reverse transcription-PCR and Sanger sequencing.ResultsFive patients from four different families were each homozygous for a four base intronic deletion in the gene TTC7A, immediately adjacent to a consensus GT splice donor site. The deletion was demonstrated to have deleterious effects on splicing causing the skipping of the attendant upstream coding exon, thereby leading to a predicted severe protein truncation. Parents were heterozygous carriers of the deletion in these families and in two additional families segregating affected cases. In a seventh family, an affected case was compound heterozygous for the same 4bp deletion and a second missense mutation p.L823P, also predicted as pathogenic. No other sequenced genes possessed deleterious variants explanatory for all patients in the cohort. Neither mutation was seen in a large set of control chromosomes.ConclusionsBased on our genetic results, TTC7A is the likely causal gene for MIA.

Original publication

DOI

10.1136/jmedgenet-2012-101483

Type

Journal article

Journal

Journal of medical genetics

Publication Date

05/2013

Volume

50

Pages

324 - 329

Addresses

Centre de Recherche du CHU Ste-Justine, University of Montreal, Montreal, Quebec, Canada

Keywords

Humans, Intestinal Atresia, Proteins, Pedigree, Sequence Alignment, Sequence Analysis, DNA, Amino Acid Sequence, Base Sequence, Homozygote, Mutation, Missense, Molecular Sequence Data, Quebec, Exome, Ethnicity