Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH

Scott, Tiana M.; Campbell, Ian; Hernández-García, Andrés; Lalani, Seema R.; Liu, Pengfei; Shaw, Chad A.; Rosenfeld, Jill A.; Scott, Daryl A.

doi:10.1136/jmedgenet-2020-107317

Cited by 30 publications

(66 citation statements)

References 40 publications

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“…Genetic contributions to CDH appeared heterogeneous. Advances in genomics, coupled with functional studies in animal models, are increasingly identifying the causes of CDH in both familial and sporadic cases [243][244][245]. Through these approaches, we are beginning to elucidate the mechanisms and molecular pathways that are responsible for diaphragm and lung development abnormalities in CDH patients.…”

Section: Discussionmentioning

confidence: 99%

Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

Cannata

Grassi

Perrone

et al. 2021

IJMS

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Congenital diaphragmatic hernia (CDH) is a relatively common major life-threatening birth defect that results in significant mortality and morbidity depending primarily on lung hypoplasia, persistent pulmonary hypertension, and cardiac dysfunction. Despite its clinical relevance, CDH multifactorial etiology is still not completely understood. We reviewed current knowledge on normal diaphragm development and summarized genetic mutations and related pathways as well as cellular mechanisms involved in CDH. Our literature analysis showed that the discovery of harmful de novo variants in the fetus could constitute an important tool for the medical team during pregnancy, counselling, and childbirth. A better insight into the mechanisms regulating diaphragm development and genetic causes leading to CDH appeared essential to the development of new therapeutic strategies and evidence-based genetic counselling to parents. Integrated sequencing, development, and bioinformatics strategies could direct future functional studies on CDH; could be applied to cohorts and consortia for CDH and other birth defects; and could pave the way for potential therapies by providing molecular targets for drug discovery.

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Section: Discussionmentioning

confidence: 99%

Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

Cannata

Grassi

Perrone

et al. 2021

IJMS

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“…By looking at subsets of two large CNV studies [ 8 , 10 ] the fraction of causal CNVs being de novo can be estimated up to 80%. Similarly, the fraction of causal variants being de novo could be estimated around 50% [ 15 ]. However, these estimations are based on small sample sizes only.…”

Section: Discussionmentioning

confidence: 99%

“…An additional 3-10% of patients present with known monogenic syndromes. More recent sequencing studies have identified de novo damaging variants in known and novel CDH-associated genes in 10-30% of CDH patients [11][12][13][14][15][16]. Furthermore, is has been shown that the presence of a likely damaging de novo variant in a patient is associated with higher mortality and overall worse clinical outcome [17].…”

Section: Introductionmentioning

confidence: 99%

The Role of De Novo Variants in Patients with Congenital Diaphragmatic Hernia

Bendixen

Reutter

2021

Genes

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The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number variations (CNVs), and variants in a large panel of CDH-associated genes, both de novo and inherited, have been described. Due to impaired reproductive fitness, especially of syndromic CDH patients, and still significant mortality rates, the contribution of de novo variants to the genetic background of CDH is assumed to be high. This assumption is supported by the relatively low recurrence rate among siblings. Advantages in high-throughput genome-wide genotyping and sequencing methods have recently facilitated the detection of de novo variants in CDH. This review gives an overview of the known de novo disease-causing variants in CDH patients.

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“…In our cohort, only a few familial cases are known (<1%). Still, CDH is described to segregate through families (1) and/or present as a monogenetic disorder following autosomal dominant (53,(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109), autosomal recessive (62,110), or X-linked (111)(112)(113) inheritance patterns.…”

Section: Cdh Is a Complex Genetic Disordermentioning

confidence: 99%

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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Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH

Cited by 30 publications

References 40 publications

Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

The Role of De Novo Variants in Patients with Congenital Diaphragmatic Hernia

Unraveling the Genetics of Congenital Diaphragmatic Hernia: An Ongoing Challenge

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