title: Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.
abstract: BACKGROUND
  Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects.
  
  
  OBJECTIVE
  We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families.
  
  
  METHODS
  We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA.
  
  
  RESULTS
  Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA.
  
  
  CONCLUSIONS
  We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: A. Nocivelli Institute for Molecular Medicine, Pediatric Clinic, University of Brescia, and the Section of Genetics, Department of Pathology Spedali Civili, Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giliani
authors.affiliation: A. Nocivelli Institute for Molecular Medicine, Pediatric Clinic, University of Brescia, and the Section of Genetics, Department of Pathology Spedali Civili, Brescia, Italy.
authors.forename: Gaetana
authors.initials: G
authors.lastname: Lanzi
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: George I
authors.initials: GI
authors.lastname: Mias
authors.affiliation: Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, Mass.
authors.forename: Kerry
authors.initials: K
authors.lastname: Dobbs
authors.affiliation: Department of Transfusion Medicine, Boston Children's Hospital, Boston, Mass.
authors.forename: John
authors.initials: J
authors.lastname: Manis
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Hogune
authors.initials: H
authors.lastname: Im
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Gallagher
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Phanstiel
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Ghia
authors.initials: G
authors.lastname: Euskirchen
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lacroute
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Keith
authors.initials: K
authors.lastname: Bettinger
authors.affiliation: A. Nocivelli Institute for Molecular Medicine, Pediatric Clinic, University of Brescia, and the Section of Genetics, Department of Pathology Spedali Civili, Brescia, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Moratto
authors.affiliation: Division of Hematology and Oncology, Boston Children's Hospital, Boston, Mass.
authors.forename: Katja
authors.initials: K
authors.lastname: Weinacht
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Torino, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Montin
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Torino, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gallo
authors.affiliation: USC Patologia Neonatale, Ospedali Riuniti di Bergamo, Bergamo, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mangili
authors.affiliation: Division of Pediatric Hematology-Oncology, Spedali Civili Brescia, Brescia, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Porta
authors.affiliation: Division of Pediatric Hematology-Oncology, Spedali Civili Brescia, Brescia, Italy.
authors.forename: Lucia D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: USC Patologia Neonatale, Ospedali Riuniti di Bergamo, Bergamo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pedretti
authors.affiliation: Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.affiliation: Department of Surgery, Ibn-Sina Hospital, Kuwait City, Kuwait.
authors.forename: Wasmi
authors.initials: W
authors.lastname: Alfahdli
authors.affiliation: New England Newborn Screening Program, University of Massachusetts Medical School, Worcester, Mass.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Comeau
authors.affiliation: Department of Internal Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pa.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Traister
authors.affiliation: Division of Hematology-Oncology, Boston Children's Hospital, Boston, Mass.
authors.forename: Sung-Yun
authors.initials: SY
authors.lastname: Pai
authors.affiliation: Clinical Immunology and Allergology, Spedali Civili Brescia, Brescia, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Carella
authors.affiliation: Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif. Electronic address: knadeau@stanford.edu.
authors.forename: Kari C
authors.initials: KC
authors.lastname: Nadeau
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, Calif. Electronic address: mpsnyder@stanford.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, Mass; Harvard Stem Cell Institute, Harvard Medical School, Boston, Mass. Electronic address: Luigi.Notarangelo@childrens.harvard.edu.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D000818:Animals; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007409:Intestinal Atresia / Q000235:genetics*; D007422:Intestines / Q000002:abnormalities*; D008297:Male; D051379:Mice; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D011506:Proteins; D012333:RNA, Messenger; C505359:TTC7 protein, mouse; C583818:TTC7A protein, human
keywords: CID-MIA; Combined immunodeficiency with multiple intestinal atresias; GATK; Genome Analysis Toolkit; Graft-versus-host disease; GvHD; HCT; Hematopoietic cell transplantation; Indels; Insertions and/or deletions; NMD; Nonsense-mediated decay; SCID; SNV; Severe combined immunodeficiency; Single nucleotide variant; T-cell receptor excision circle; TREC; TTC7A; Tetratricopeptide repeat domain 7A; WES; Whole-exome sequencing; tetratricopeptide repeat domain 7A; thymus; whole-exome sequencing