Whole-exome sequencing reveals a monogenic cause in 56% of individuals with laterality disorders and associated congenital heart defects

Yoav Bolkier, Ortal Barel, Dina Marek-Yagel, Danit Atias-Varon, Maayan Kagan, Amir Vardi, David Mishali, Uriel Katz, Yishay Salem, Tal Tirosh-Wagner, Jeffrey M. Jacobson, Annick Raas-Rothschild, Odelia Chorin, Aviva Eliyahu, Yarden Sarouf, Omer Shlomovitz, Alvit Veber, Nechama Shalva, Elisheva Javasky, Yishay Ben MosheOrna Staretz-Chacham, Gideon Rechavi, Shrikant Mane, Yair Anikster, Asaf Vivante, Ben Pode-Shakked

    Research output: Contribution to journalArticlepeer-review

    16 Scopus citations


    Background The 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. Objective We 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. Methods Detailed 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. Results Using 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. Conclusions Our 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.

    Original languageEnglish
    Pages (from-to)691-696
    Number of pages6
    JournalJournal of Medical Genetics
    Issue number7
    StatePublished - 1 Jul 2022


    • Hereditary
    • and neonatal diseases and abnormalities
    • congenital
    • heart defects

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)


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