The Role of de novo Variants in Patients with Congenital Diaphragmatic Hernia

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

10.1101/2021.06.01.21257928 ◽

2021 ◽

Author(s):

Lu Qiao ◽

Le Xu ◽

Lan Yu ◽

Julia Wynn ◽

Rebecca Hernan ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Rare Variants ◽

De Novo ◽

Disease Genes ◽

Risk Genes ◽

Association Analyses ◽

Significant Enrichment ◽

Coding Variants

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (Lon Peptidase 1, Mitochondrial) and ALYREF (Aly/REF Export Factor) as novel candidate CDH genes based on de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 cases and 11,220 ancestry-matched population controls and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in familial cases. Approximately 3% of our CDH cohort was heterozygous with ultra-rare predicted damaging variants in LONP1 who have a range of clinical phenotypes including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium specific deletion of Lonp1 die immediately after birth and have reduced lung growth and branching that may at least partially explain the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

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Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia

Human Genetics ◽

10.1007/s00439-017-1774-y ◽

2017 ◽

Vol 136 (6) ◽

pp. 679-691 ◽

Cited By ~ 16

Author(s):

Mauro Longoni ◽

Frances A. High ◽

Hongjian Qi ◽

Maliackal P. Joy ◽

Regis Hila ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

De Novo ◽

Genome Wide

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Role of Ultrasound-Based Prenatal Prediction of Pulmonary Function in Congenital Diaphragmatic Hernia: Does It Have Prognostic Significance Postnatally?

The Journal of Obstetrics and Gynecology of India ◽

10.1007/s13224-016-0922-y ◽

2016 ◽

Vol 67 (1) ◽

pp. 33-36 ◽

Cited By ~ 1

Author(s):

Nupur Shah ◽

Sujit Chowdhary ◽

Anita Kaul

Keyword(s):

Pulmonary Function ◽

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Prognostic Significance

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The role of ECMO in the management of congenital diaphragmatic hernia

Seminars in Perinatology ◽

10.1053/j.semperi.2019.07.005 ◽

2020 ◽

Vol 44 (1) ◽

pp. 151166

Author(s):

Peter T. Yu ◽

Howard C. Jen ◽

Samuel Rice-Townsend ◽

Yigit S. Guner

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia

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De novo frameshift mutation inCOUP-TFII(NR2F2) in human congenital diaphragmatic hernia

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.37830 ◽

2016 ◽

Vol 170 (9) ◽

pp. 2457-2461 ◽

Cited By ~ 15

Author(s):

Frances A. High ◽

Pooja Bhayani ◽

Jay M. Wilson ◽

Carol J. Bult ◽

Patricia K. Donahoe ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Frameshift Mutation ◽

De Novo

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Systematic analysis of copy number variation associated with congenital diaphragmatic hernia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1714885115 ◽

2018 ◽

Vol 115 (20) ◽

pp. 5247-5252 ◽

Cited By ~ 8

Author(s):

Qihui Zhu ◽

Frances A. High ◽

Chengsheng Zhang ◽

Eliza Cerveira ◽

Meaghan K. Russell ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Candidate Genes ◽

Birth Defects ◽

Diaphragmatic Hernia ◽

Copy Number ◽

Large Scale ◽

De Novo ◽

Comparative Genomic ◽

High Morbidity ◽

Systematic Analysis

Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to identify CNVs within 140 regions in 196 patients and 987 healthy controls, and identified six significant CNVs that were either unique to patients or enriched in patients compared with controls. These CDH-associated CNVs reveal high-priority candidate genes including HLX, LHX1, and HNF1B. We also discuss CNVs that are present in only one patient in the cohort but have additional evidence of pathogenicity, including extremely rare large and/or de novo CNVs. The candidate genes within these predicted disease-causing CNVs form functional networks with other known CDH genes and play putative roles in DNA binding/transcription regulation and embryonic development. These data substantiate the importance of CNVs in the etiology of CDH, identify CDH candidate genes and pathways, and highlight the importance of ongoing analysis of CNVs in the study of CDH and other structural birth defects.

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Contribution of retrotransposition to developmental disorders

Nature Communications ◽

10.1038/s41467-019-12520-y ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 10

Author(s):

Eugene J. Gardner ◽

Elena Prigmore ◽

Giuseppe Gallone ◽

Petr Danecek ◽

Kaitlin E. Samocha ◽

...

Keyword(s):

Developmental Disorders ◽

De Novo ◽

Purifying Selection ◽

Selective Constraint ◽

Protein Coding ◽

Genome Wide ◽

De Novo Gene ◽

The Impact ◽

Transcribed Sequences

Abstract Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

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