Abstract
Van der Woude syndrome (VWS) shows an autosomal dominant pattern of inheritance with two known candidate genes, IRF6 and GRHL3. In this study, by employing genome-wide linkage analyses on two VWS affected families, we report the cosegregation of an intronic rare variant in NOL4 in one family, and a haplotype consisting of three variants in the noncoding region of IRF6 (introns 1, 8 and 3\('\)UTR) in the other family. Using mouse, as well as human embryos as a model, we demonstrate the expression of NOL4 in the lip and palate primordia during their development. Luciferase, as well as miRNA-transfection assays show decline in the expression of mutant NOL4 construct due to the creation of a binding site for hsa-miR-4796-5p. In family 2, the noncoding region IRF6 haplotype turns out to be the candidate possibly by diminishing its IRF6 expression to half of its normal activity. Thus, here we report a new candidate gene (NOL4) and a haplotype of IRF6 for VWS, and highlight the genetic heterogeneity of this disorder in the Indian population.
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Acknowledgements
We gratefully acknowledge the support of the VWS families and all the volunteers for their participation in the study. We thank Professors Pradeep Sinha and S. Ganesh, IIT-Kanpur, for providing the microarray facility, and Dr Nisha Rani Agrawal, Department of Obstetrics and Gynaecology, IMS, BHU for providing the aborted foetal sample. The microarray facility in BHU was provided by the Interdisciplinary School of Life Sciences and NGS is the Central facility of the University. This work was supported by the Programme support grant from the Department of Biotechnology, India, to RR. PK was awarded fellowship by the Council of Scientific and Industrial Research, New Delhi, India.
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Kumari, P., Ali, A., Singh, S.K. et al. Genetic heterogeneity in Van der Woude syndrome: identification of NOL4 and IRF6 haplotype from the noncoding region as candidates in two families. J Genet 97, 275–285 (2018). https://doi.org/10.1007/s12041-018-0903-2
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DOI: https://doi.org/10.1007/s12041-018-0903-2