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.
- and neonatal diseases and abnormalities
- heart defects
Data availability statement
Data are available upon reasonable request from the corresponding author.
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AV and BP-S are joint senior authors.
YB, OB and DM-Y contributed equally.
Contributors BP-S, YB, YA and AVi initiated the study and substantially contributed to its conception and design, acquisition, analysis and interpretation of the data, and wrote the manuscript. MK, AVa, DM, UK, YS, TT-W, JMJ, AR, OC, AE, YS, OS, AVe, NS, YBM, OS-C, YA and BP-S contributed to the recruitment of patients and acquisition of data. OB, DM-Y, DA-V, EJ, GR and SM contributed to the WES data analysis and interpretation. In addition, all authors critically reviewed the manuscript and approved the submitted version.
Funding The Yale Center for Mendelian Genomics (NIH M#UM1HG006504) is funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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