Whole-exome sequencing reveals a monogenic cause in 56% of individuals with laterality disorders and associated congenital heart defects
| Autor: | Yarden Sarouf, Amir Vardi, Ben Pode-Shakked, Yishay Ben Moshe, Alvit Veber, Gideon Rechavi, Yair Anikster, Dina Marek-Yagel, Odelia Chorin, Annick Raas-Rothschild, Shrikant Mane, Yoav Bolkier, Yishay Salem, Danit Atias-Varon, Omer Shlomovitz, Elisheva Javasky, Tal Tirosh-Wagner, Uriel Katz, Jeffrey M. Jacobson, Orna Staretz-Chacham, Nechama Shalva, Ortal Barel, David Mishali, Maayan Kagan, Asaf Vivante, Aviva Eliyahu |
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| Rok vydání: | 2021 |
| Předmět: |
Heart Defects
Congenital Proband Heart malformation C21orf59 Heterotaxy Syndrome Cohort Studies symbols.namesake Exome Sequencing Genetics Humans Medicine Disease-causing Mutation Genetics (clinical) Exome sequencing Primary ciliary dyskinesia Sanger sequencing biology business.industry Homozygote Membrane Proteins medicine.disease Mutation symbols biology.protein Intercellular Signaling Peptides and Proteins business Heterotaxy |
| Zdroj: | Journal of Medical Genetics. 59:691-696 |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmedgenet-2021-107775 |
| Popis: | BackgroundThe molecular basis of heterotaxy and congenital heart malformations associated with disruption of left–right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far.ObjectiveWe sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab–Muslim descent, using next-generation sequencing techniques.MethodsDetailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families.ResultsUsing WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46.ConclusionsOur findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families. |
| Databáze: | OpenAIRE |
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