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.

AB - 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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