Whole-Exome Sequencing for Identification of Genetic Variants Involved in Vitamin D Metabolic Pathways in Families With Vitamin D Deficiency in Saudi Arabia

Shatha Alharazy; Muhammad Imran Naseer; Eman Alissa; Margaret Denise Robertson; Susan Lanham-New; Adeel G Chaudhary

doi:10.3389/fgene.2021.677780

Whole-Exome Sequencing for Identification of Genetic Variants Involved in Vitamin D Metabolic Pathways in Families With Vitamin D Deficiency in Saudi Arabia

Front Genet. 2021 Jun 8:12:677780. doi: 10.3389/fgene.2021.677780. eCollection 2021.

Authors

Shatha Alharazy¹, Muhammad Imran Naseer^{2

3}, Eman Alissa⁴, Margaret Denise Robertson⁵, Susan Lanham-New⁵, Adeel G Chaudhary^{2

3

6}

Affiliations

¹ Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
² Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
³ Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
⁴ Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
⁶ Centre for Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

Abstract

Background: Numerous research studies have found an association between vitamin D (vitD) status and single-nucleotide polymorphisms (SNPs) in genes involved in vitD metabolism. It is notable that the influence of these SNPs on 25-hydroxyvitamin D [25(OH)D] levels might vary in different populations. In this study, we aimed to explore for genetic variants in genes related to vitD metabolism in families with vitD deficiency in Saudi Arabia using whole-exome sequencing (WES).

Methods: This family-based WES study was conducted for 21 families with vitD deficiency (n = 39) in Saudi Arabia. WES was performed for DNA samples, then resulting WES data was filtered and a number of variants were prioritized and validated by Sanger DNA sequencing.

Results: Several missense variants in vitD-related genes were detected in families. We determined two variants in low-density lipoprotein 2 gene (LRP2) with one variant (rs2075252) observed in six individuals, while the other LRP2 variant (rs4667591) was detected in 13 subjects. Single variants in 7-dehydrocholesterol reductase (DHCR7) (rs143587828) and melanocortin-1 receptor (MC1R) (rs1805005) genes were observed in two subjects from two different families. Other variants in group-specific component (GC), cubilin (CUBN), and calcium-sensing receptor (CASR) gene were found in index cases and controls. Polymorphisms in GC (rs9016) and CASR (rs1801726) were found in the majority of family cases (94 and 88%), respectively.

Conclusion: In vitD-deficient families in Saudi Arabia, we were able to detect a number of missense exonic variants including variants in GC (rs9016), CUBN (rs1801222), CASR (rs1801726), and LRP2 (rs4667591). However, the existence of these variants was not different between affected family members and non-affected controls. Additionally, we were able to find a mutation in DHCR7 (rs143587828) and a polymorphism in LRP2 (rs2075252), which may affect vitD levels and influence vitD status. Further studies are now required to confirm the association of these variants with vitD deficiency.

Keywords: Saudi Arabia; family study; polymorphisms; variants; vitamin D; vitamin D deficiency; vitamin D metabolism; whole-exome sequencing.