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

Qiao, Li; Xu, Le; Yu, Lan; Wynn, Julia; Hernan, Rebecca; Zhou, Xueya; Farkouh-Karoleski, Christiana; Krishnan, Usha; Khlevner, Julie; De, Aliva; Zygmunt, Annette; Crombleholme, Timothy M.; Lim, Foong Yen; Needelman, Howard; Cusick, Robert A.; Mychaliska, George B.; Warner, Brad W.; Wagner, Amy J.; Danko, Melissa E.; Chung, Dai H.; Potoka, Douglas A.; Kosiński, Przemysław; McCulley, David J.; Elfiky, Mahmoud; Azarow, Kenneth S.; Fialkowski, Elizabeth; Schindel, David T.; Soffer, Samuel Z.; Lyon, Jane B.; Zalieckas, Jill M.; Vardarajan, Badri N.; Aspelund, Guðrún; High, Frances A.; Sun, Xin; Donahoe, Patricia K.; Shen, Yufeng; Chung, Wendy K.

doi:10.1016/j.ajhg.2021.08.011

Cited by 23 publications

(29 citation statements)

References 94 publications

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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%

“…For 1q41–1q42 deletions, one duplication disrupting the HLX gene and subsequent HLX gene variants have been described ( 15 , 18 , 125 – 128 ). Constraint coding regions are enriched for de novo variants ( 104 ), and using variant evaluation guidelines of rare de novo changes in these types of constraint genes ( 129 ) result in a likely pathogenic or pathogenic classification, especially if variants result in reduced amounts of protein.…”

Section: Cdh Is a Complex Genetic Disordermentioning

confidence: 99%

“…Detecting a deleterious variant in a gene in multiple patients helps prioritizing candidate genes for function evaluation and studies using animal models. In a large cohort ( n = 827), seven syndromic and four recurrent CNVs were identified ( 104 ). Some of these have already been associated with CDH; e.g., 17q12 deletions, 16p13.1 duplications, 22q11 deletions, and 21q22 duplications.…”

Section: From Pathogenic Alteration To Cdhmentioning

confidence: 99%

“…Some of these have already been associated with CDH; e.g., 17q12 deletions, 16p13.1 duplications, 22q11 deletions, and 21q22 duplications. Furthermore, 87 CNVs were de novo , of which 54 were large (>2 Mb) deletions ( 104 ). Although non-recurrent, at least a proportion of these large de novo deletions are likely to be related to the patient's phenotype.…”

Section: From Pathogenic Alteration To Cdhmentioning

confidence: 99%

“…Ten genes were enriched for de novo variants, of which mitochondrial lon peptidase 1 ( LONP1 ) and Aly/REF export factor ( ALYREF ) were the most promising candidate disease genes. LONP1, MYRF as well as ZFPM2 reached or approached genome wide significance when a variant burden test was performed for all deleterious changes (i.e., including inherited variants) ( 104 ). Combining multiple “omics” and in-vitro translational approaches can potentially bridge the gap between genetic findings and animal models.…”

Section: From Pathogenic Alteration To Cdhmentioning

confidence: 99%

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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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