Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene
| Autor: | Julie Khlevner, Julia Wynn, Frances A. High, Usha Krishnan, Aliva De, Xin Sun, Jane B. Lyon, Lan Yu, David J. McCulley, Howard Needelman, Gudrun Aspelund, Yufeng Shen, Timothy M. Crombleholme, Elizabeth A. Fialkowski, Kenneth S. Azarow, Rebecca Hernan, Vincent Duron, Le Xu, Christiana Farkouh-Karoleski, Douglas A. Potoka, Foong-Yen Lim, Xueya Zhou, Brad W. Warner, Dai Chung, Mahmoud Elfiky, Jill M. Zalieckas, Samuel Z. Soffer, David T. Schindel, Melissa E. Danko, Wendy K. Chung, Badri N. Vardarajan, Patricia K. Donahoe, Przemyslaw Kosinski, Amy J. Wagner, Lu Qiao, Robert A. Cusick, George B. Mychaliska, Annette Zygmunt |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Proband
Male Inbred C57BL Medical and Health Sciences congenital diaphragmatic hernia Pathogenesis Cohort Studies Craniofacial Abnormalities Congenital Mice ATP-Dependent Proteases Infant Mortality Hip Dislocation 2.1 Biological and endogenous factors Eye Abnormalities Aetiology de novo variants Lung Genetics (clinical) Growth Disorders Hernias Genetics Pediatric Genetics & Heredity Mice Knockout LONP1 High mortality Biological Sciences Phenotype Pedigree medicine.anatomical_structure Female DNA Copy Number Variations Knockout Mutation Missense Risk gene Biology Osteochondrodysplasias Article Mitochondrial Proteins Rare Diseases Clinical Research medicine Animals Humans Gene Hip Dislocation Congenital Tooth Abnormalities Human Genome Congenital diaphragmatic hernia Perinatal Period - Conditions Originating in Perinatal Period medicine.disease Mice Inbred C57BL Good Health and Well Being ALYREF Case-Control Studies Mutation Congenital Structural Anomalies Missense Digestive Diseases Hernias Diaphragmatic Congenital Diaphragmatic |
| Zdroj: | Am J Hum Genet American journal of human genetics, vol 108, iss 10 |
| ISSN: | 1537-6605 |
| Popis: | 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-associated 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 candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals 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 affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 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, most likely because of the observed severe reduction of lung growth, a known contributor to 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|