Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes

Breuer K, Riedhammer KM, Mueller N, Schaidinger B, Dombrowsky G, Dittrich S, Zeidler S, Bauer UMM, Westphal DS, Meitinger T, Dakal TC, Hitz MP, Breuer J, Reutter H, Hilger AC, Hoefele J (2022)

Publication Type: Journal article

Publication year: 2022

Journal

European Journal of Human Genetics Nature Publishing Group: Open Access Hybrid Model Option B

DOI: 10.1038/s41431-022-01100-2

Abstract

The birth prevalence of laterality defects is about 1.1/10,000 comprising different phenotypes ranging from situs inversus totalis to heterotaxy, mostly associated with complex congenital heart defects (CHD) and situs abnormalities such as intestinal malrotation, biliary atresia, asplenia, or polysplenia. A proportion of laterality defects arise in the context of primary ciliary dyskinesia (PCD) accompanied by respiratory symptoms or infertility. In this study, exome sequencing (ES) was performed in 14 case-parent trios/quattros with clinical exclusion of PCD prior to analysis. Moreover, all cases and parents underwent detailed clinical phenotyping including physical examination, echocardiography by a skilled paediatric cardiologist and abdominal ultrasound examinations not to miss mildly affected individuals. Subsequent survey of the exome data comprised filtering for monoallelic de novo, rare biallelic, and X-linked recessive variants. In two families, rare variants of uncertain significance (VUS) in PKD1L1 and ZIC3 were identified. Both genes have been associated with laterality defects. In two of the remaining families, biallelic variants in LMBRD1 and DNAH17, respectively, were prioritized. In another family, an ultra-rare de novo variant in WDR47 was found. Extensive exome survey of 2,109 single exomes of individuals with situs inversus totalis, heterotaxy, or isolated CHD identified two individuals with novel monoallelic variants in WDR47, but no further individuals with biallelic variants in DNAH17 or LMBRD1. Overall, ES of 14 case-parent trios/quattros with cardiovascular laterality defects identified rare VUS in two families in known disease-associated genes PKD1L1 and ZIC3 and suggests DNAH17, LMBRD1, and WDR47 as potential genes involved in laterality defects.

Authors with CRIS profile

Sven Dittrich Professur für Kinderkardiologie

Involved external institutions

Universitätsklinikum Bonn DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Asklepios Kliniken DE Germany (DE) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) DE Germany (DE) Mohanlal Sukhadia University / University of Udaipur IN India (IN)

How to cite

APA:

Breuer, K., Riedhammer, K.M., Mueller, N., Schaidinger, B., Dombrowsky, G., Dittrich, S.,... Hoefele, J. (2022). Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes. European Journal of Human Genetics. https://doi.org/10.1038/s41431-022-01100-2

MLA:

Breuer, Katinka, et al. "Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes." European Journal of Human Genetics (2022).

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