Targeted next-generation sequencing reveals novel and known variants of thrombophilia associated genes in Saudi patients with venous thromboembolism

Mohammad Athar; Ibrahim S Ghita; Amani A Albagenny; Zainularifeen Abduljaleel; Ghulam Shadab; Ahmed Elsendiony; Saeed H Halawani; Mohammad M Alkazmi; Khalid Alquthami; Mohammad M Alkhuzae; Abdulaziz A Althebyani; Neda M Bogari; Anas Dannoun; Faisal A Al-Allaf

doi:10.1016/j.cca.2021.05.012

Targeted next-generation sequencing reveals novel and known variants of thrombophilia associated genes in Saudi patients with venous thromboembolism

Clin Chim Acta. 2021 Aug:519:247-254. doi: 10.1016/j.cca.2021.05.012. Epub 2021 May 18.

Affiliations

¹ Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia. Electronic address: mabedar@uqu.edu.sa.
² Hematology Department, Al-Noor Specialist Hospital, Makkah, Saudi Arabia.
³ Laboratory and Blood Bank Department, Al-Noor Specialist Hospital, Makkah, Saudi Arabia.
⁴ Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.
⁵ Cytogenetics and Molecular Toxicology Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh 202002, India.
⁶ Department of Hematology and Immunology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
⁷ Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.

PMID: 34015304
DOI: 10.1016/j.cca.2021.05.012

Abstract

Background: Thrombophilia is a substantial source of indisposition and mortality in several countries, including Arab populations. Deep venous thrombosis (DVT) with or without pulmonary embolism (PE) is the prevalent clinical manifestation of thrombophilia. While many genetic risk factors for DVT are known, almost all associated with hemostasis, many genetic factors remain unexplained. Nowadays, Next Generation Sequencing (NGS) offers a potential solution that allows several candidate genes to be analyzed simultaneously at a reasonable expense.

Methods: We performed variant screening in the thrombophilia associated genes in Factor V Leiden (FVL) mutation-negative patients using Ion Torrent Next-generation sequencing (NGS). Ion AmpliSeq panel for 18 genes was designed. Twenty-nine unrelated patients with idiopathic VTE were recruited for NGS.

Results: We were able to identify 19 variants (1 novel and 18 previously reported) in 10 out of 18 targeted genes. Pathogenic variants were identified in 22 patients demonstrating mutation detection rates of 76%. Previously reported variants in the F5, MTHFR, PROS1, PROC, F8, F9, SERPINA10, SERPIND1, and HRG genes were recognized in 21 patients. More than one variant in the targeted genes was detected in some of the patients with VTE. We identified SERPINA10 recurrent variant p.(R88*) in seven patients representing 32% of VTE cases. Additionally, we report one novel variant c.356G > T, p.(G119V) in the F7 gene, considered to be pathogenic in this study.

Conclusions: Our studies finding illustrates the ability of targeted next-generation sequencing to uncover uncommon/unknown genetic variants that may predispose to thrombophilia. The finding of the novel variant in the F7 gene extends the spectrum of variants affecting thrombosis. While a comparatively small number of subjects have been included in our cohort, the findings summarize the possible genetic features of thrombophilia.

Keywords: Deep vein thrombosis; Factor V Leiden; Next-generation sequencing; Thrombophilia; Variant; Venous thromboembolism.

MeSH terms

Factor V / genetics
High-Throughput Nucleotide Sequencing
Humans
Methylenetetrahydrofolate Reductase (NADPH2) / genetics
Saudi Arabia
Thrombophilia* / genetics
Venous Thromboembolism* / genetics

Substances

Factor V
Methylenetetrahydrofolate Reductase (NADPH2)