Dataset Information

Whole Exome Sequencing Identifies TTC7A Mutations for Combined Immunodeficiency with Intestinal Atresia

ABSTRACT:

Combined Immunodeficiency with Multiple Intestinal Atresias (CID-MIA) is a rare genetic disorder with the cause previously unknown. Symptoms of CID-MIA include atresias in the small and/or large intestine, as well as immunodeficiency. In this study, we sequenced the whole exome of 5 unrelated CID-MIA patients as well as their healthy family members, and identified deleterious homozygous or compound heterozygous mutations in the gene TTC7A in all the 5 patients, as well as in 3 additional patients with Sanger sequencing. Our findings strongly indicate TTC7A dysfunction to be the cause for CID-MIA.

PROVIDER: phs000641.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.

Chen Rui R Giliani Silvia S Lanzi Gaetana G Mias George I GI Lonardi Silvia S Dobbs Kerry K Manis John J Im Hogune H Gallagher Jennifer E JE Phanstiel Douglas H DH Euskirchen Ghia G Lacroute Philippe P Bettinger Keith K Moratto Daniele D Weinacht Katja K Montin Davide D Gallo Eleonora E Mangili Giovanna G Porta Fulvio F Notarangelo Lucia D LD Pedretti Stefania S Al-Herz Waleed W Alfahdli Wasmi W Comeau Anne Marie AM Traister Russell S RS Pai Sung-Yun SY Carella Graziella G Facchetti Fabio F Nadeau Kari C KC Snyder Michael M Notarangelo Luigi D LD

The Journal of allergy and clinical immunology 20130704 3

<h4>Background</h4>Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects.<h4>Objective</h4>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.<h4>Methods</h4>We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belong ...[more]

PMID: 23830146

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Project description:Background: Severe combined immunodeficiency (SCID) is characterized by arrested T lymphocyte production and B lymphocyte dysfunction, resulting in life-threatening infections. Early diagnosis of SCID through population-based newborn screening (NBS) optimizes clinical management and outcomes, and also permits identification of previously unknown factors essential for human lymphocyte development. Methods: SCID was detected, prior to onset of infections, by NBS of T cell receptor excision circles, a biomarker for thymic output. Upon confirmation, the affected baby was treated by allogeneic hematopoietic cell transplantation (HCT). The genetic cause was sought by exome sequencing of the patient and parents, followed by functional analysis of a prioritized candidate gene using human hematopoietic stem cells (HSC) and zebrafish embryos. Results: An infant with leaky SCID, craniofacial and dermal abnormalities, and absent corpus callosum had his immune deficit fully corrected by HCT. Exome sequencing revealed a heterozygous, de novo, missense mutation pN441K in BCL11B. The mutant Bcl11b protein had dominant negative activity, abrogating the ability of wild type Bcl11b to bind DNA, arresting T cell lineage development and disrupting HSC migration, revealing a novel function of Bcl11b. The patientâs defects, recapitulated in Bcl11b-deficient zebrafish, were reversed by ectopic expression of intact, but not mutant, human BCL11B. Conclusions: Newborn screening facilitated treatment and identification of a novel etiology for human SCID. Coupling exome sequencing with candidate gene evaluation in human HSC and in zebrafish revealed that a constitutional BCL11B mutation causes human multisystem anomalies with SCID, while also revealing a novel, pre-thymic role for Bcl11b in hematopoietic progenitors. 3 samples were analyzed in duplicate, Sample 1 was human HSC transduced with GFP only lentivirus which served as controls, Sample 2 was human HSC transduced with lentivirus expressing FLAG-tagged WT BCL11B and GFP, Sample 3 was human HSC transduced with lentivirus expressing FLAG-tagged mutant BCL11B and GFP

Dataset Information

Whole Exome Sequencing Identifies TTC7A Mutations for Combined Immunodeficiency with Intestinal Atresia

Publications

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.

Similar Datasets

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