Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

Abstract

Summary The diaphragm is critical for respiration and separation of the thoracic and abdominal cavities, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The genetic etiology of CDH is complex. Single-nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs) in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple individuals and mutated genes are incompletely penetrant. This suggests that multiple genetic variants in combination, other not-yet-investigated classes of variants, and/or nongenetic factors contribute to CDH etiology. However, no studies have comprehensively investigated in affected individuals the contribution of all possible classes of variants throughout the genome to CDH etiology. In our study, we used a unique cohort of four individuals with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood and deep whole-genome sequencing to assess germline and somatic de novo and inherited SNVs, indels, and SVs. In each individual we found a different mutational landscape that included germline de novo and inherited SNVs and indels in multiple genes. We also found in two individuals a 343 bp deletion interrupting an annotated enhancer of the CDH-associated gene GATA4 , and we hypothesize that this common SV (found in 1%–2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial.

Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia

“…A significant challenge in the diagnosis and treatment of CDH has been low yields of genetic testing, with a pathogenic genetic change identified in only 30% of cases (Yu et al, 2020). Our results further support recent studies that employ WGS which found a diverse array of mutational types that cause CDH (SNV/INDELs, SVs, and splice site changes) and show the utility of WGS as a first‐line diagnostic tool (Bogenschutz et al, 2020; Sweeney et al, 2018).…”

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene

“…Typically, each gene or copy-number variant (CNV) associated with CDH accounts for at most 1%-2% of affected individuals. 9 The full spectrum of genomic variants has been associated with CDH, including chromosome aneuploidies (10%), copy-number variants (CNVs) (3%-10%), monogenic conditions (10%-22%), and emerging evidence for oligogenic causes 1 (CNVs and individual genes 10 ).…”

3D in vitro Models of Pathological Skeletal Muscle: Which Cells and Scaffolds to Elect?

“…Congenital diaphragmatic hernia (CDH) is a malformation in which the diaphragm fails to properly form, resulting in the abdominal viscera invasion into the thoracic cavity during embryonic development ( Sefton et al, 2018 ). Despite the moderate incidence (1:3,000 new-born), the etiology of the disease is not completely understood due to the heterogeneous and multifactorial players ( Bogenschutz et al, 2020 ). Indeed, high proportion of CDH cases may be due to new dominant mutations, but epigenetic events could also be a causal factor ( Pober et al, 2005 ).…”