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.

/pdf/whole-exome-sequencing-identifies-tetratricopeptide-repeat-3v6xlhou0f.pdf

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

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.

https://jmg.bmj.com/content/jmedgenet/50/5/324.full.pdf

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

The increasing incidence of pediatric inflammatory bowel disease, coupled with the efficiency of whole-exome sequencing, has led to the identification of tetratricopeptide repeat domain 7A (TTC7A) as a steward of intestinal health. TTC7A deficiency is an autosomal-recessively inherited disease. In the 5 years since the original description, more than 50 patients with more than 20 distinct disease-causing TTC7A mutations have been identified. Patients show heterogenous intestinal and immunologic disease manifestations, including but not limited to multiple intestinal atresias, very early onset inflammatory bowel disease, loss of intestinal architecture, apoptotic enterocolitis, combined immunodeficiency, and various extraintestinal features related to the skin and/or hair. The focus of this review is to highlight trends in patient phenotypes and to consolidate functional data related to the role of TTC7A in maintaining intestinal homeostasis. TTC7A deficiency is fatal in approximately two thirds of patients, and, as more patients continue to be discovered, elucidating the comprehensive role of TTC7A could show druggable targets that may benefit the growing cohort of individuals suffering from inflammatory bowel disease.

TTC7A: Steward of Intestinal Health.

Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort.

Fifty-two infants with intestinal atresia are reviewed.Bile-stained vomiting was the first symptom (53%),and delayed meconium in 7 cases.The atresia located in jejunum (9),ileum (37),colon(5) and scattered all over the digestive tract in one case.The type of the atresia included:type Ⅰ (membranous) in 6 cases,type Ⅱ(blind end) 30,type Ⅲ (multiple) 13,and type Ⅳ (Apple-peel) 3.Associated volvulus and meconium peritonitis were found in 42.3%.Total survival rate of this series was 76.92%.The outcome of enterostomy was poor.Twenty-six cases were operated on by tapering of the proximal loop and end to end anastomosis with a survival rate of 88.45%,while the survival rate to those by simple resection and anastomosis was 68.75%.It is essential to resect and taper the proximal dilated blind loop and make an end to end anastomosis.Timing of operation,associated malformations,operative complications,reoperations,and length of the residual intestine are the important factors in prognosis.

Key words: 
Intestinal atresia; Intestinal obstruction; Acute abdomen

Intestinal Atresia

Hereditary multiple intestinal atresia (HMIA), a presumed autosomal recessive disorder, is an unusual and rare form of recurrent intestinal atresia which can be associated with severe combined immunodeficiency (SCID). The combination of HMIA and SCID is invariably lethal. The authors describe this fatal association in two siblings. The parents are consanguineous and have three other normal healthy children. Both index cases had abnormal antenatal ultrasounds and were symptomatic after birth. The final diagnosis of HMIA with SCID was confirmed in both siblings. They were never able to receive enteral feeds, remained totally dependent on parenteral nutrition, had repeated episodes of sepsis and died after a very difficult neonatal intensive care course. In this article we have reviewed the clinical course and outcome of both cases. The existing literature on multiple intestinal atresia, HMIA and HMIA with immunodeficiency is also reviewed.

/pdf/hereditary-multiple-intestinal-atresia-hmia-with-severe-1ylnso60yt.pdf

Hereditary multiple intestinal atresia (HMIA) with severe combined immunodeficiency (SCID): a case report of two siblings and review of the literature on MIA, HMIA and HMIA with immunodeficiency over the last 50 years

Yasser Ali Hussein Ali

Papers

Hereditary multiple intestinal atresia (HMIA) with severe combined immunodeficiency (SCID): a case report of two siblings and review of the literature on MIA, HMIA and HMIA with immunodeficiency over the last 50 years