Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia

Abstract

Background Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified. Objective Identify genomic alterations that contribute to the development of diaphragmatic defects. Methods A cohort of 45 unrelated patients with CDH or diaphragmatic eventrations were screened for genomic alterations by array comparative genomic hybridization (aCGH) or SNP-based copy number analysis. Results Genomic alterations that were likely to have contributed to the development of CDH were identified in eight patients. Inherited deletions of ZFPM2 were identified in two patients with isolated diaphragmatic defects and a large de novo 8q deletion overlapping the same gene was found in a patient with non-isolated CDH. A de novo microdeletion of chromosome 1q41q42 and two de novo microdeletions on chromosome 16p11.2 were identified in patients with non-isolated CDH. Duplications of distal 11q and proximal 13q were found in a patient with non-isolated CDH and a de novo single gene deletion of FZD2 was also identified in a patient with a partial pentalogy of Cantrell phenotype. Conclusions Haploinsufficiency of ZFPM2 can cause dominantly inherited isolated diaphragmatic defects with incomplete penetrance. Our data define a new minimal deleted region for CDH on 1q41q42, provide evidence for the existence of CDH-related genes on chromosomes 16p11.2, 11q23-24 and 13q12 and suggest a possible role for FZD2 and Wnt signaling in pentalogy of Cantrell phenotypes. These results demonstrate the clinical utility of screening for genomic alterations in individuals with both isolated and non-isolated diaphragmatic defects.

Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics

“…Third, the majority of variants identified were inherited from an apparently unaffected parent, consistent with decreased penetrance for many of these putative causative genes. A model of decreased penetrance has been proposed for several other known CDHcausing genes, such as ZFPM2 (12,13). Because this study did not include parental exomes, we are unable to determine the true contribution of de novo mutations to the pathogenesis of CDH.…”

“…We filtered our exome results for variants in genes mapped within "hotspots" for chromosomal deletions in patients with CDH, i.e., regions reported in the literature to be deleted in two or more individuals with CDH. The following seven chromosomal regions were given priority because they contained breakpoints precisely defined by molecular cytogenetics: 1q41-q42.12, 4p16.3, 6p25.2-p25.3, 8p23.1, 8q22.3-q23.1, 15q26.1-q26.3, and 16p11.2 (13)(14)(15)(16)(17). Fifteen genes in these critical regions have been proposed to play a role in CDH, seven of which were also included in the analysis above as CDH-causing genes.…”

Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula

“…However, these include more prevalent CNVs and not a selected subset. In other diseases, de novo CNVs have a much higher impact, for example, congenital diaphragmatic hernia 35 or intellectual disability. 36 The de novo CNVs seen in this study are nonoverlapping and some of them do not affect genes with clear association to the abnormalities seen in patients.…”

Copy number analysis of 413 isolated talipes equinovarus patients suggests role for transcriptional regulators of early limb development

“…Although its predominant use has been in studying individuals with neuropsychiatric disorders or multiple congenital anomalies, our research adds to the literature supporting the use of CNV analysis to study isolated birth defects. [23][24][25]48 Copy number analysis can be particularly effective for parsing out genetic pathways when, as in our case, it can be used Table 3.…”

“…However, few studies have used CNV analysis to study isolated human birth defects. 18,[22][23][24][25] Rare CNVs may serve to identify candidate genes that are more typically altered by other mechanisms (ie point mutations) or they may delineate a microdeletion syndrome. Alternatively, common CNVs may be significantly more frequent in a patient population, exerting only small to modest effects on disease susceptibility.…”