title: Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia.
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.
authors: Centre de Recherche du CHU Ste-Justine, University of Montreal, Montreal, Quebec, Canada
authors: Mark E
authors: ME
authors: Samuels
authors: Jacek
authors: J
authors: Majewski
authors: Najmeh
authors: N
authors: Alirezaie
authors: Isabel
authors: I
authors: Fernandez
authors: Ferran
authors: F
authors: Casals
authors: Natalie
authors: N
authors: Patey
authors: Hélène
authors: H
authors: Decaluwe
authors: Isabelle
authors: I
authors: Gosselin
authors: Elie
authors: E
authors: Haddad
authors: Alan
authors: A
authors: Hodgkinson
authors: Youssef
authors: Y
authors: Idaghdour
authors: Valerie
authors: V
authors: Marchand
authors: Jacques L
authors: JL
authors: Michaud
authors: Marc-André
authors: MA
authors: Rodrigue
authors: Sylvie
authors: S
authors: Desjardins
authors: Stéphane
authors: S
authors: Dubois
authors: Francoise
authors: F
authors: Le Deist
authors: Philip
authors: P
authors: Awadalla
authors: Vincent
authors: V
authors: Raymond
authors: Bruno
authors: B
authors: Maranda
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D005006:Ethnicity / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007409:Intestinal Atresia / Q000208:ethnology / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D011792:Quebec; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D011506:Proteins; C583818:TTC7A protein, human