Identification of CACNA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance
J Hum Genet.
Liaqat K1,2, Schrauwen I2, Raza SI3,4, Lee K2, Hussain S2,4, Chakchouk I2, Nasir A4, Acharya A2, Abbe I2, Umair M4,5, Ansar M4, Ullah I4,6, Shah K4,7; University of Washington Center for Mendelian Genomics, Bamshad MJ8,9, Nickerson DA8, Ahmad W4, Leal SM10.
1 Department of Biotechnology, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Islamabad, Pakistan.
2 Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
3 Department of Biochemistry, HBS Medical College, Shaheed Zulfiqar Ali Bhutto Medical University Islamabad, Islamabad, Pakistan.
4 Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Islamabad, Pakistan.
5 Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard-Health Affairs (MNGHA), P.O. Box 3660, Riyadh, 11481, Saudi Arabia.
6 Department of Chemistry, Shaheed Benazir Bhutto University, Sheringal, Upper Dir, Pakistan.
7 Department of Environmental Sciences, Comsats University Islamabad, Abbottabad Campus, Islamabad, Pakistan.
8 Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA.
9 Department of Pediatrics, University of Washington, Seattle, WA, USA.
10 Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. firstname.lastname@example.org.
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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.