Identification of Novel KMT2B Variants in Chinese Dystonia Patients via Whole-Exome Sequencing.

Jun Ma,Yingmai Yang,Lin Wang,Shanglin Li,Xinhua Wan

doi:10.3389/fneur.2019.00729

Abstract

Background: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Recently mutations in lysine-specific histone methyltransferase 2B (KMT2B) gene have been reported to be associated with early-onset progressive dystonia.Methods: We performed whole-exome sequencings (WES) in a cohort of early-onset dystonia patients from China. Bioinformatics analysis and cosegregation testings were conducted to select candidate causal variants. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines.Results: Three novel KMT2B variants were identified, including p.Q1359* in patient 1, p.R1487AfsTer7 in patient 2, and p.R152W in patient 3. Among these variants, the nonsense variant p.Q1359* and the frameshift variant p.R1487AfsTer7 showed high pathogenicity and were rated as pathogenic according to the ACMG guideline. Regarding the phenotypes of these two patients with pathogenic variants, patient 2 showed the similar presentation as reported whereas patient 1 seemly harbored the atypical presentations, including later onset age, atypical sites of onset and milder degree of dystonia.Conclusions: We further report three dystonia patients with novel variants in KMT2B and expand the spectrums of genotype and phenotype of KMT2B.

Highlights

Dystonia is known as a group of clinically and etiologically heterogeneous disorders characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both [1]
We screened KMT2B in a cohort of early-onset Chinese dystonia patients by whole-exome sequencing to expand the current knowledge on this gene
All these patients were required to be diagnosed as dystonia with onset of dystonia before 26 years old

Summary

Introduction

Dystonia is known as a group of clinically and etiologically heterogeneous disorders characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both [1]. With the advent of next-generation sequencing (NGS) technology, an expanding spectrum of dystonia associated genes have been identified [2]. In 2016, two groups independently reported mutations in a newly identified gene, lysine-specific histone methyltransferase 2B (KMT2B) in patients with early-onset generalized dystonia [3, 4]. We screened KMT2B in a cohort of early-onset Chinese dystonia patients by whole-exome sequencing to expand the current knowledge on this gene. Dystonia is a movement disorder with high clinical and genetic heterogeneity. Mutations in lysine-specific histone methyltransferase 2B (KMT2B) gene have been reported to be associated with early-onset progressive dystonia

Methods

Results

Conclusion