Abstract
Sinoatrial node dysfunction and deafness (SANDD) syndrome is rare and characterized by a low heart beat and severe-to-profound deafness. Additional features include fatigue, dizziness, and episodic syncope. The sinoatrial node (SAN) drives heart automaticity and continuously regulates heart rate. The CACNA1D gene encoding the Cav1.3 protein expressed in inner hair cells, atria and SAN, induces loss-of-function in channel activity and underlies SANDD. To date, only one variant c.1208_1209insGGG:p.(G403_V404insG) has been reported for SANDD syndrome. We studied five Pakistani families with SANDD and characterized a new missense variant p.(A376V) in CACNA1D in one family, and further characterized the founder variant p.(G403_V404insG) in four additional pedigrees. We show that affected individuals in the four families which segregate p.(G403_V404insG) share a 1.03 MB haplotype on 3p21.1 suggesting they share a common distant ancestor. In conclusion, we identified new and known variants in CACNA1D in five Pakistani families with SANDD. This study is of clinical importance as the CACNA1D founder variant is only observed in families from the Khyber Pakhtunkhwa (KPK) province, in Pakistan. Therefore, screening patients with congenital deafness for SAN dysfunction in this province could ensure adequate follow-up and prevent cardiac failure associated with SAN.
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Acknowledgements
We would like to thank the families for their participation in this study. This work was supported by the Higher Education Commission of Pakistan (to W.A.) and National Institutes of Health (NIH)-National Institute of Deafness and other Disorders grants R01 DC011651 and R01 DC003594 (to S.M.L). “Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268201200008I”. Exome sequencing performed at the University of Washington Center for Mendelian Genomics was funded by the NIH–National Human Genome Research Institute grant UM1 HG006493 (to D.A.N., M.J.B., and S.M.L.).
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Supplementary data: The Supplementary information in this paper includes the list of members of the University of Washington Center for Mendelian Genomics (UWCMG) study group and two figures (Supplementary figure 1; Supplementary figure 2).
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Liaqat, K., Schrauwen, I., Raza, S.I. et al. Identification of CACNA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance. J Hum Genet 64, 153–160 (2019). https://doi.org/10.1038/s10038-018-0542-8
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DOI: https://doi.org/10.1038/s10038-018-0542-8
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