Mutation Analysis of MYORG in a Chinese Cohort With Primary Familial Brain Calcification

Yi-Heng Zeng,Miao Zhao,Xin-Xin Guo,Hui-Zhen Su,Yun-Lu Li,Wan-Jin Chen,Bi-Wei Lin,Xiang-Ping Yao,Lu-Lu Lai

doi:10.3389/fgene.2021.732389

Abstract

Primary familial brain calcification (PFBC) is a progressive neurological disorder manifesting as bilateral brain calcifications in CT scan with symptoms as parkinsonism, dystonia, ataxia, psychiatric symptoms, etc. Recently, pathogenic variants in MYORG have been linked to autosomal recessive PFBC. This study aims to elucidate the mutational and clinical spectrum of MYORG mutations in a large cohort of Chinese PFBC patients with possible autosomal recessive or absent family history. Mutational analyses of MYORG were performed by Sanger sequencing in a cohort of 245 PFBC patients including 21 subjects from 10 families compatible with a possibly autosomal-recessive trait and 224 apparently sporadic cases. In-depth phenotyping and neuroimaging features were investigated in all patients with novel MYORG variants. Two nonsense variants (c.442C > T, p. Q148*; c.972C > A, p. Y324*) and two missense variants (c.1969G>C, p. G657R; c.2033C > G, p. P678R) of MYORG were identified in four sporadic PFBC patients, respectively. These four novel variants were absent in gnomAD, and their amino acid were highly conserved, suggesting these variants have a pathogenic impact. Patients with MYORG variants tend to display a homogeneous clinical spectrum, showing extensive brain calcification and parkinsonism, dysarthria, ataxia, or vertigo. Our findings supported the pathogenic role of MYORG variants in PFBC and identified two pathogenic variants (c.442C > T, c.972C > A), one likely pathogenic variant (c.2033C > G), and one variant of uncertain significance (c.1969G>C), further expanding the genetic and phenotypic spectrum of PFBC-MYORG.

Highlights

Primary familial brain calcification (PFBC), widely known as Fahr’s disease, is a rare inherited neurodegenerative disease characterized by bilateral calcium deposits in the basal ganglia and/or other brain regions, in the absence of other secondary causes for brain calcification (Manyam, 2005)
All sporadic patients were previously tested for variants of all AD-PFBC genes by Sanger sequencing, and no pathogenic variants were detected (SLC20A2, PDGFRB, PDGFB, and XPR1)
Eight MYORG variants were identified in six sporadic cases, while four of the eight variants were previously reported

Summary

Introduction

Primary familial brain calcification (PFBC), widely known as Fahr’s disease, is a rare inherited neurodegenerative disease characterized by bilateral calcium deposits in the basal ganglia and/or other brain regions, in the absence of other secondary causes for brain calcification (Manyam, 2005). PFBC is inherited in an autosomal dominant manner (AD-PFBC); to date, four autosomal dominant PFBC-associated genes have been identified, including SLC20A2, PDGFRB, PDGFB, and XPR1 (Wang et al, 2012; Nicolas et al, 2013b; Keller et al, 2013; Legati et al, 2015). We have first reported disease-causing mutations in MYORG gene (MIM: 618255) for the autosomal recessive form of PFBC (AR-PFBC) (MIM #618317) (Yao et al, 2018). Another team identified JAM2 as a gene related to autosomal recessive PFBC, further supporting the recessive pathogenic gene as a factor in PFBC pathogenesis (Cen et al, 2020)

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