Pathogenic NOTCH3 Variants Are Frequent Among the Korean General Population

Chul-Hoo Kang; Young Mee Kim; Yang-Ji Kim; Su-Jeong Hong; Do Yoon Kim; Hyun Goo Woo; Young Ree Kim; Joong-Goo Kim; Jung Seok Lee; Mi Hee Kong; Hyeon Ju Kim; Jay Chol Choi

doi:10.1212/NXG.0000000000000639

Pathogenic NOTCH3 Variants Are Frequent Among the Korean General Population

Neurol Genet. 2021 Dec 6;7(6):e639. doi: 10.1212/NXG.0000000000000639. eCollection 2021 Dec.

Authors

Affiliation

¹ Department of Neurology (C.-H.K., J.-G.K., J.S.L., J.C.C.), Jeju National University Hospital, Jeju National University School of Medicine; Department of Biochemistry (Y.M.K.), School of Medicine; Institute of Medical Science (Y.-J.K., S.-J.H., J.C.C.), Jeju National University, Korea; Department of Physiology (D.Y.K., H.G.W.), School of Medicine; Department of Biomedical Science (D.Y.K., H.G.W.), Graduate School, Ajou University, Suwon, Republic of Korea; Department of Laboratory Medicine (Y.R.K.), School of Medicine, Jeju National University; Department of Family Medicine (M.H.K., H.J.K.), Jeju National University Hospital; and Department of Family Medicine (M.H.K., H.J.K.), School of Medicine, Jeju National University, Korea.

Abstract

Objective: This study aimed to determine the frequency of pathogenic NOTCH3 variants among Koreans.

Methods: In this cross-sectional study, we queried for pathogenic NOTCH3 variants in 2 Korean public genome databases: the Korean Reference Genome Database (KRGDB) and the Korean Genome Project (Korea1K). In addition, we screened the 3 most common pathogenic NOTCH3 variants (p.Arg75Pro, p.Arg544Cys, and p.Arg578Cys) for 1,000 individuals on Jeju Island, where the largest number of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported in Korea.

Results: The pathogenic NOTCH3 variant (p.Arg544Cys) was found in 0.12% of sequences in the KRGDB, and 3 pathogenic variants (p.Arg75Pro, p.Arg182Cys, and p.Arg544Cys) were present in 0.44% of the Korea1K database. Of the 1,000 individuals on Jeju Island, we found 2 cysteine-altering NOTCH3 variants (p.Arg544Cys variant in 9 and p.Arg578Cys in 1 individual) in 1.00% of the participants (95% confidence interval: 0.48%-1.83%). The presence of cysteine-altering NOTCH3 variants was significantly associated with a history of stroke (p < 0.001).

Discussion: Pathogenic NOTCH3 variants are frequently found in the general Korean population. Such a high prevalence of pathogenic variants could threaten the brain health of tens of thousands to hundreds of thousands of older adults in Korea.