Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia - PubMed (original) (raw)

doi: 10.1136/jmedgenet-2012-101483. Epub 2013 Feb 19.

Jacek Majewski, Najmeh Alirezaie, Isabel Fernandez, Ferran Casals, Natalie Patey, Hélène Decaluwe, Isabelle Gosselin, Elie Haddad, Alan Hodgkinson, Youssef Idaghdour, Valerie Marchand, Jacques L Michaud, Marc-André Rodrigue, Sylvie Desjardins, Stéphane Dubois, Francoise Le Deist, Philip Awadalla, Vincent Raymond, Bruno Maranda

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Free PMC article

Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia

Mark E Samuels et al. J Med Genet. 2013 May.

Free PMC article

Abstract

Background: Congenital 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.

Methods: We 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.

Results: Five 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.

Conclusions: Based on our genetic results, TTC7A is the likely causal gene for MIA.

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Figures

Figure 1

Figure 1

Multiple intestinal atresia pedigrees F1–F7. F1–F6 are from Centre Hospitalier de l'Université Laval cohort, F7 is from Centre Hospitalier Ste-Justine cohort. Affecteds are shown as filled diamonds, status of 4 bp deletion in exon 7 only is shown in F1–F6 as a delta sign, status of the 4 bp exon 7 deletion and p.L823P missense in exon 20 are shown in F7. Horizontal dash or question mark means no genotype was obtained. Probands who underwent exome sequencing are starred. One affected was previously reported (Bilodeau et al, case 11). To preserve confidentiality sex is not shown, and children are not in obligate order of birth.

Figure 2

Figure 2

Multiple sequence alignment of putative TTC7A orthologs, showing the C-terminus of the protein. Residue L823 is boxed in all orthologs, and the mutation p.L823P (according to the human amino acid numbering) is shown above the top row.

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