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

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

    Research output: Contribution to journalArticle

    Abstract

    Background: Congenital multiple intestinal atresia (MIA) is a severe, fatal neonataldisorder, 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 thestudy 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 wasdemonstrated 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.

    Original languageEnglish (US)
    Pages (from-to)324-329
    Number of pages6
    JournalJournal of Medical Genetics
    Volume50
    Issue number5
    DOIs
    StatePublished - Feb 21 2013

    Fingerprint

    Exome
    Mutation
    Genes
    Exons
    Intestinal Atresia
    RNA Splice Sites
    Large Intestine
    Gene Deletion
    Missense Mutation
    Reverse Transcription
    Small Intestine
    Multiple Intestinal Atresia
    Consensus
    Chromosomes
    Parents
    Phenotype
    Polymerase Chain Reaction
    Survival

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

    Cite this

    Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. / Samuels, Mark E.; Majewski, Jacek; Alirezaie, Najmeh; Fernandez, Isabel; Casals, Ferran; Patey, Natalie; Decaluwe, Hélène; Gosselin, Isabelle; Haddad, Elie; Hodgkinson, Alan; Idaghdhour, Youssef; Marchand, Valerie; Michaud, Jacques L.; Rodrigue, Marc André; Desjardins, Sylvie; Dubois, Stéphane; Le Deist, Francoise; Awadalla, Philip; Raymond, Vincent; Maranda, Bruno.

    In: Journal of Medical Genetics, Vol. 50, No. 5, 21.02.2013, p. 324-329.

    Research output: Contribution to journalArticle

    Samuels, ME, Majewski, J, Alirezaie, N, Fernandez, I, Casals, F, Patey, N, Decaluwe, H, Gosselin, I, Haddad, E, Hodgkinson, A, Idaghdhour, Y, Marchand, V, Michaud, JL, Rodrigue, MA, Desjardins, S, Dubois, S, Le Deist, F, Awadalla, P, Raymond, V & Maranda, B 2013, 'Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia', Journal of Medical Genetics, vol. 50, no. 5, pp. 324-329. https://doi.org/10.1136/jmedgenet-2012-101483
    Samuels, Mark E. ; Majewski, Jacek ; Alirezaie, Najmeh ; Fernandez, Isabel ; Casals, Ferran ; Patey, Natalie ; Decaluwe, Hélène ; Gosselin, Isabelle ; Haddad, Elie ; Hodgkinson, Alan ; Idaghdhour, Youssef ; Marchand, Valerie ; Michaud, Jacques L. ; Rodrigue, Marc André ; Desjardins, Sylvie ; Dubois, Stéphane ; Le Deist, Francoise ; Awadalla, Philip ; Raymond, Vincent ; Maranda, Bruno. / Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. In: Journal of Medical Genetics. 2013 ; Vol. 50, No. 5. pp. 324-329.
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    abstract = "Background: Congenital multiple intestinal atresia (MIA) is a severe, fatal neonataldisorder, 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 thestudy 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 wasdemonstrated 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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    T1 - Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia

    AU - Samuels, Mark E.

    AU - Majewski, Jacek

    AU - Alirezaie, Najmeh

    AU - Fernandez, Isabel

    AU - Casals, Ferran

    AU - Patey, Natalie

    AU - Decaluwe, Hélène

    AU - Gosselin, Isabelle

    AU - Haddad, Elie

    AU - Hodgkinson, Alan

    AU - Idaghdhour, Youssef

    AU - Marchand, Valerie

    AU - Michaud, Jacques L.

    AU - Rodrigue, Marc André

    AU - Desjardins, Sylvie

    AU - Dubois, Stéphane

    AU - Le Deist, Francoise

    AU - Awadalla, Philip

    AU - Raymond, Vincent

    AU - Maranda, Bruno

    PY - 2013/2/21

    Y1 - 2013/2/21

    N2 - Background: Congenital multiple intestinal atresia (MIA) is a severe, fatal neonataldisorder, 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 thestudy 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 wasdemonstrated 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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