Germline but not somatic de novo mutations are common in human congenital diaphragmatic hernia

Matsunami, Nori; Shanmugam, Hari; Baird, Lisa; Stevens, Jeff; Byrne, Janice L. B.; Barnhart, Douglas C.; Rau, Carrie; Feldkamp, Marcia L.; Yoder, Bradley A.; Leppert, M.; Yost, H. Joseph; Brunelli, Luca

doi:10.1002/bdr2.1223

Cited by 12 publications

(14 citation statements)

References 31 publications

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“…Our analysis of the diaphragm revealed multiple somatic variants in the diaphragm’s connective tissue, but none in coding or annotated enhancers, and so these somatic variants are unlikely to be deleterious. A previous study 130 also found no evidence of damaging somatic variants, although this study examined tissue sampled around the periphery of the herniated region and so did not specifically sample the connective tissue that mouse genetic studies predict to be a cellular source of CDH. 17 , 33 , 34 While our study did not find potentially damaging somatic variants in the diaphragm’s connective tissue, we have established an effective discovery strategy.…”

Section: Discussionmentioning

confidence: 99%

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

Bogenschutz

Fox

Farrell

et al. 2020

Human Genetics and Genomics Advances

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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.

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Section: Discussionmentioning

confidence: 99%

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

Bogenschutz

Fox

Farrell

et al. 2020

Human Genetics and Genomics Advances

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“…NR2F2 maps to the 15q26 microdeletion hotspot. NR2F2 is also expressed in the PPF, and a truncating variant in the gene has been identified in two patients with CDH and an atrial septal defect and coarctation/hypoplastic mitral valve, respectively (High et al, 2016;Matsunami et al, 2018). NR2F2 in complex with RERE, Ep300, and an RA receptor promote transcriptional activation of gene targets of RA signaling (Vilhais-Neto et al, 2010).…”

Section: Ra-dependent Gene Expressionmentioning

confidence: 99%

Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects

Beecroft

Ayala²,

McGillivray

et al. 2021

Human Mutation

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This study shows a causal association between ALDH1A2 variants and a novel, severe multiple congenital anomaly syndrome in humans that is neonatally lethal due to associated pulmonary hypoplasia and respiratory failure. In two families, exome sequencing identified compound heterozygous missense variants in ALDH1A2. ALDH1A2 is involved in the conversion of retinol (vitamin A) into retinoic acid (RA), which is an essential regulator of diaphragm and cardiovascular formation during embryogenesis. Reduced RA causes cardiovascular, diaphragmatic, and associated pulmonary defects in several animal models, matching the phenotype Sarah J. Beecroft and Marcos Ayala joint first authors.

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“…In line with this, whole genome sequencing did not find causative somatic variants in diaphragm biopsies (96,97). In contrast, germline de novo variants are often present (33,(96)(97)(98). Females have a higher burden of de novo variants (98), suggesting a female protective model.…”

Section: Cdh Is a Complex Genetic Disordermentioning

confidence: 62%

“…The mutated diaphragmatic cells might not have survived in sufficient quantities and, therefore, be undetectable with sequencing technologies (95). In line with this, whole genome sequencing did not find causative somatic variants in diaphragm biopsies (96,97). In contrast, germline de novo variants are often present (33,(96)(97)(98).…”

Section: Cdh Is a Complex Genetic Disordermentioning

confidence: 73%

Unraveling the Genetics of Congenital Diaphragmatic Hernia: An Ongoing Challenge

et al. 2022

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Congenital diaphragmatic hernia (CDH) is a congenital structural anomaly in which the diaphragm has not developed properly. It may occur either as an isolated anomaly or with additional anomalies. It is thought to be a multifactorial disease in which genetic factors could either substantially contribute to or directly result in the developmental defect. Patients with aneuploidies, pathogenic variants or de novo Copy Number Variations (CNVs) impacting specific genes and loci develop CDH typically in the form of a monogenetic syndrome. These patients often have other associated anatomical malformations. In patients without a known monogenetic syndrome, an increased genetic burden of de novo coding variants contributes to disease development. In early years, genetic evaluation was based on karyotyping and SNP-array. Today, genomes are commonly analyzed with next generation sequencing (NGS) based approaches. While more potential pathogenic variants are being detected, analysis of the data presents a bottleneck—largely due to the lack of full appreciation of the functional consequence and/or relevance of the detected variant. The exact heritability of CDH is still unknown. Damaging de novo alterations are associated with the more severe and complex phenotypes and worse clinical outcome. Phenotypic, genetic—and likely mechanistic—variability hampers individualpatient diagnosis, short and long-term morbidity prediction and subsequent care strategies. Detailed phenotyping, clinical follow-up at regular intervals and detailed registries are needed to find associations between long-term morbidity, genetic alterations, and clinical parameters. Since CDH is a relatively rare disorder with only a few recurrent changes large cohorts of patients are needed to identify genetic associations. Retrospective whole genome sequencing of historical patient cohorts using will yield valuable data from which today's patients and parents will profit Trio whole genome sequencing has an excellent potential for future re-analysis and data-sharing increasing the chance to provide a genetic diagnosis and predict clinical prognosis. In this review, we explore the pitfalls and challenges in the analysis and interpretation of genetic information, present what is currently known and what still needs further study, and propose strategies to reap the benefits of genetic screening.

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Germline but not somatic de novo mutations are common in human congenital diaphragmatic hernia

Cited by 12 publications

References 31 publications

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

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

Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects

Unraveling the Genetics of Congenital Diaphragmatic Hernia: An Ongoing Challenge

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