Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes

Li, Qiao; Wynn, Julia; Yu, Lan; Hernan, Rebecca; Zhou, Xueya; Duron, Vincent; Aspelund, Guðrún; Farkouh-Karoleski, Christiana; Zygumunt, Annette; Krishnan, Usha; Nees, Shannon N.; Khlevner, Julie; Lim, Foong Yen; Crombleholme, Timothy M.; Cusick, Robert A.; Azarow, Kenneth S.; Danko, Melissa E.; Chung, Dai H.; Warner, Brad W.; Mychaliska, George B.; Potoka, Douglas A.; Wagner, Amy J.; Soffer, Samuel Z.; Schindel, David T.; McCulley, David J.; Shen, Yufeng; Chung, Wendy K.

doi:10.1038/s41436-020-0908-0

Cited by 27 publications

(50 citation statements)

References 28 publications

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“…Each participating site also procured approval from their local IRB and signed informed consent A total of 827 cases and their parents had whole genome (WGS) or exome sequencing in the current study. A subset of trios (n=574) has been described in our previous study 3,9 .…”

Section: Participant Recruitment and Control Datasetsmentioning

confidence: 99%

“…Pulmonary hypoplasia, cardiac displacement and intestinal herniation were considered to be part of the diaphragm defect sequence and were not considered independent malformations. Data on the child's current and past health including family history of congenital anomalies, postoperative pulmonary hypertension, mortality or survival status prior to initial discharge, extracorporeal membrane oxygenation (ECMO) intake were gathered as described previously 3 .…”

Section: Participant Recruitment and Control Datasetsmentioning

confidence: 99%

“…Congenital diaphragmatic hernia (CDH) affects approximately 3 per 10,000 neonates 1,2 . Approximately 40% of CDH cases occur with additional congenital anomalies besides common secondary anomalies (dextrocardia and lung hypoplasia) 3 . The most common additional anomalies 4,5 are structural heart defects (11-15%), musculoskeletal malformations (15-20%) including limb deficiency, club foot, and omphalocele 6 .…”

Section: Introductionmentioning

confidence: 99%

“…However, anomalies of almost every organ have been described in association with CDH. Despite advances in care including improved prenatal diagnosis, fetal interventions, extracorporeal membrane oxygenation (ECMO) and gentle ventilation, CDH continues to be associated with at least 20% mortality and significant long-term morbidity including feeding difficulties, pulmonary hypertension and other respiratory complications, and neurocognitive deficits 3,7,8 .…”

Section: Introductionmentioning

confidence: 99%

“…We also demonstrated a higher burden of de novo likely damaging (LD) variants in females compared to males supporting a "female protective model" 9 . Most recently, in a cohort with long term developmental outcome data 3 , we demonstrated that de novo likely damaging (LD) variants are associated with poorer neurodevelopmental outcomes as well as a higher prevalence of pulmonary hypertension (PH).…”

Section: Introductionmentioning

confidence: 99%

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

Qiao

Liu

et al. 2021

Preprint

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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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Section: Participant Recruitment and Control Datasetsmentioning

confidence: 99%

Section: Participant Recruitment and Control Datasetsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Qiao

Liu

et al. 2021

Preprint

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MYRF: A unique transmembrane transcription factor‐ from proteolytic self‐processing to its multifaceted roles in animal development

Qi,

Xu,

Shen

et al. 2024

BioEssays

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The Myelin Regulator Factor (MYRF) is a master regulator governing myelin formation and maintenance in the central nervous system. The conservation of MYRF across metazoans and its broad tissue expression suggest it has functions extending beyond the well‐established role in myelination. Loss of MYRF results in developmental lethality in both invertebrates and vertebrates, and MYRF haploinsufficiency in humans causes MYRF‐related Cardiac Urogenital Syndrome, underscoring its importance in animal development; however, these mechanisms are largely unexplored. MYRF, an unconventional transcription factor, begins embedded in the membrane and undergoes intramolecular chaperone mediated trimerization, which triggers self‐cleavage, allowing its N‐terminal segment with an Ig‐fold DNA‐binding domain to enter the nucleus for transcriptional regulation. Recent research suggests developmental regulation of cleavage, yet the mechanisms remain enigmatic. While some parts of MYRF's structure have been elucidated, others remain obscure, leaving questions about how these motifs are linked to its intricate processing and function.

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Couples experiences of receiving uncertain results following prenatal microarray or exome sequencing: A mixed‐methods systematic review

et al. 2020

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Background: Tests in pregnancy such as chromosomal microarray analysis and exome sequencing are increasing diagnostic yield for fetal structural anomalies, but have greater potential to result in uncertain findings. This systematic review investigated the experiences of prospective parents about receiving uncertain results from these tests.Methods: A systematic search of three electronic databases was conducted. Data extraction was performed for studies that met the eligibility and quality criteria.Results were synthesised following the principles of thematic analysis.Results: Fourteen studies (10 qualitative, 4 quantitative) were included. Findings were grouped into three overarching themes. Sources of uncertainty included the testing procedure, the diagnosis and prognosis, and health professionals' own uncertainty. The clinical impact of the uncertainty included parents struggling to make clinical decisions with the information available, the emotional impact included decisional-regret, shock, worry and feeling overwhelmed. To manage the uncertainty, parents sought support from healthcare professionals, friends, family, the internet and other parents as well as remaining hopeful.Conclusions: Prospective parents experience a myriad of uncertainties in the prenatal setting, which must be handled sensitively. Future research should explore optimal ways of managing uncertainty to minimise harm. Recommendations are made for discussing uncertainty during pre-and post-test counseling. | BACKGROUNDFetal anomalies occur in 2% to 5% of pregnancies and cause around 21% of perinatal deaths. 1,2,3 Initially, prenatal testing for fetal anomalies was limited to karyotyping and targeted genetic testing. 4 Chromosomal microarray analysis (CMA), which is able to evaluate the sub-microscopic structure of chromosomes is now being offered routinely in many countries, and prenatal exome sequencing (ES), which provides resolution down to the single base-pair, is beginning to be used clinically to increase diagnostic rates. 5 There are a number of benefits in getting a result from prenatal testing. This includes the potential to provide a definitive diagnosis during pregnancy which can then inform genetic counselling, pregnancy and delivery management, and pre-and post-natal care. 6,7

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Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes

Cited by 27 publications

References 28 publications

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

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

MYRF: A unique transmembrane transcription factor‐ from proteolytic self‐processing to its multifaceted roles in animal development

Couples experiences of receiving uncertain results following prenatal microarray or exome sequencing: A mixed‐methods systematic review

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