Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia

Abstract

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D,

NFX1, Its Isoforms and Roles in Biology, Disease and Cancer

“…Second, in vascular studies, familial segregation analysis revealed that NFX1 c.2519T>C (p.Leu840Pro) was associated with intracranial aneurysms, a cerebrovascular disorder; this NFX1 point mutation was found in only cases and was absent among unaffected family members [ 25 ], linking NFX1 as a genetic risk factor for these familial intracranial aneurysms. Third, in gastrointestinal development, an NFX1 novel de novo variant c.1723G>A (p.Val575Met) was found to be one of the deleterious variants in human esophageal atresia, the most common malformation of the upper digestive tract [ 26 ], suggesting a functional significance to NFX1 expression in upper digestive tract development and disease. Lastly, in metabolism and endocrinopathies, greater NFX1, with decreased HLA-DRA gene expression, was observed in obese adolescent individuals with insulin resistance compared to those who were insulin sensitive [ 27 ].…”

Heritability and De Novo Mutations in Oesophageal Atresia and Tracheoesophageal Fistula Aetiology

“…Mutations in DNA repair genes (FANC genes), genes involved in endocytic vesicular trafficking [26,27], the splicing machinery [28], and several transcription factor genes (e.g., SRY (sex determining region Y)-box 2 (SOX2), MYCN Proto-Oncogene, and BHLH Transcription Factor (MYCN)) could explain some of the aetiology of OA/TOF in patients. OA/TOF is very heterogeneous, and neither de novo mutations [26,27,29] nor de novo Copy Number Variations (CNVs) [30,31] impact a shared locus or gene frequently. However, the total contribution of these changes is substantial.…”

“…However, recently, de novo variants have been described in 218 patients, mostly singletons. Four genes (Zinc Finger Homeobox 3 (ZFHX3), ERCC Excision Repair 1, Endonuclease Non-Catalytic Subunit (ERCC1), Glutaminase (GLS), and Lysine Methyltransferase 2D (KMT2D)) had a de novo mutation in more than one patient [26,27,29].…”

“…This table was modified after [24,25], and a substantial portion of these genes was evaluated in a large cohort of patients with OA-and VACTERL-associated anomalies using a Molecular Inversion Probe Candidate gene screening [32]. Interestingly, Screening VACTERL patients including those with OA/TOF as well as exome and genome sequencing of patients did not result in high de novo rates in these genes [26,27,29,32].…”

“…Interestingly, especially complex OA/TOF seems to be affected by de novo mutation [26,27,29]. Three germ layers-endoderm, mesoderm, and ectoderm-each give rise to different organ structures.…”