<i>MYORG</i> Mutation Heterozygosity Is Associated With Brain Calcification

Chen, You; Cen, Zhidong; Chen, Xinhui; Wang, Haotian; Chen, Si; Yang, Dehao; Fu, Feng; Wang, Lebo; Liu, Peng; Wu, Hongwei; Zheng, Xiaosheng; Xie, Fei; Ouyang, Zhiyuan; Zhang, Yun; Zhou, Yongji; Huang, Xuerong; Wang, Feng; Huang, Guangsu; An, Honglei; Liang, Yubing; Hong, Weijun; Wang, An‐Li; Huang, Shuangling; Chen, Wenhai; Yin, Lili; Yang, Yan; Hu, Huang; Zeng, Ruxin; Zhao, Na; Jiang, Biao; Zhang, Baorong; Luo, Wei

doi:10.1002/mds.27973

Cited by 11 publications

(18 citation statements)

References 30 publications

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“…The clinical manifestations and neuroimaging features significantly vary among PFBC patients with mutations in different pathogenic genes. In our four patients, the brain CT findings showed widespread and abundant calcifications, which is consistent with the neuroimaging features in PFBC patients with MYORG mutations as reported by Chen et al (Chen et al, 2019;Chen et al, 2020). Compared with other pathogenic genes, brainstem calcifications affecting the pons and cerebellar atrophy could be the prominent features in MYORG mutation carriers.…”

Section: Discussionsupporting

confidence: 90%

“…We screened a total of 245 Chinese subjects including 21 subjects from 10 possibly autosomal recessive families and 224 sporadic cases. Eight MYORG variants were identified in six sporadic cases, while four of the eight variants were previously reported (c.103A > G, p.M35V; c.782_783GC > TT, p. R261L; c.1092_1097delCTTCGA, p.365_366delFD; and c.1967T > C, p. I656T) (Supplementary Figures S1A-D) (Yao et al, 2018;Forouhideh et al, 2019;Chelban et al, 2020;Chen et al, 2020). Notably, four novel variants in MYORG were identified: 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) (Figures 1A-D).…”

Section: Myorg Variants In the Primary Familial Brain Calcification Cohortmentioning

confidence: 92%

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

Zeng

Lin

et al. 2021

Front. Genet.

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Myorg Variants In the Primary Familial Brain Calcification Cohortmentioning

confidence: 92%

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

Zeng

Lin

et al. 2021

Front. Genet.

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“…Thus, MYORG mutations may exhibit dosage-dependent paraclinical and clinical penetrance, with heterozygous variants, nevertheless, being potentially disease causing. 28 Of further note, we considered every carrier of a nonbenign variant with reported brain calcification and any symptom/sign as clinically affected. However, given that some symptoms (eg, headache and depression) are very prevalent in the general population, and may not be caused by a PFBCgene variant, the penetrance of these variants may actually be lower.…”

Section: Discussionmentioning

confidence: 99%

“…However, about half of the 75 carriers of single heterozygous variants in MYORG , reportedly recessive disease gene, that we excluded from analysis (Supplementary Table S3) had calcifications of various severity and patterns, and among those, only one‐third displayed clinical symptoms/signs. Thus, MYORG mutations may exhibit dosage‐dependent paraclinical and clinical penetrance, with heterozygous variants, nevertheless, being potentially disease causing 28 . Of further note, we considered every carrier of a nonbenign variant with reported brain calcification and any symptom/sign as clinically affected.…”

Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Relations in Primary Familial Brain Calcification: Systematic MDSGene Review

et al. 2021

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A BS TRACT: This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet-derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet-derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis-regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one-third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (54%), and the penetrance of SLC20A2 and XPR1 variants (<70%) was lower in comparison to the remaining three genes (>85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomaldominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotypephenotype relations that will improve counseling of individuals with mutations in PFBC genes.

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“…Deletions adjacent to the regulatory element in the SLC20A2 coding region may also cause PFBC (Pasanen et al, 2017;Cassinari et al, 2020). SLC20A2 expression might be related to the severity of brain calcification to some extent, such as the genetic dosage effect observed in patients harboring MYORG mutations (Chen et al, 2019b(Chen et al, , 2020Grangeon et al, 2019). Some studies have also suggested a dominant negative function of SLC20A2 genetic variations (Kimura et al, 2016;Larsen et al, 2017), with bi-allelic pathogenic mutations in SLC20A2, resulting in more severe brain calcification (de Oliveira et al, 2013;Chen et al, 2019a).…”

Section: Slc20a2 and Pdgfb Dosage And Functional Effect In Brain Calcificationmentioning

confidence: 99%

Case Report: Two Novel Frameshift Mutations in SLC20A2 and One Novel Splice Donor Mutation in PDGFB Associated With Primary Familial Brain Calcification

et al. 2021

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Primary familial brain calcification (PFBC, OMIM#213600), also known as Fahr's disease, is characterized by bilateral and symmetric brain calcification in the basal ganglia (globus pallidus, caudate nucleus, and putamen), thalamus, subcortical white matter, and cerebellum. PFBC can be caused by loss-of-function mutations in any of the six known causative genes. The most common clinical manifestations include movement disorders, cognitive impairment, and neuropsychiatric signs that gradually emerge in middle-aged patients. To broaden the PFBC mutation spectrum, we examined nine members of a family with PFBC and two sporadic cases from clinical departments, and sequenced all PFBC-causative genes in the index case. Two novel frameshift mutations in SLC20A2 [NM_001257180.2; c.806delC, p.(Pro269Glnfs*49) and c.1154delG, p.(Ser385Ilefs*70)] and one novel splice donor site mutation (NM_002608.4, c.456+1G>C, r.436_456del) in PDGFB were identified in the patient cohort. c.806delC co-segregated with brain calcification and led to SLC20A2 haploinsufficiency among the affected family members. The c.456+1G>C mutation in PDGFB resulted in aberrant mRNA splicing, thereby forming mature transcripts containing an in-frame 21 base pair (bp) deletion, which might create a stably truncated protein [p.(Val146_Gln152del)] and exert a dominant negative effect on wild-type PDGFB. All three mutations were located in highly conserved regions among multiple species and predicted to be pathogenic, as evaluated by at least eight common genetic variation scoring systems. This study identified three novel mutations in SLC20A2 and PDGFB, which broadened and enriched the PFBC mutation spectrum.

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MYORG Mutation Heterozygosity Is Associated With Brain Calcification

Cited by 11 publications

References 30 publications

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

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

Genotype–Phenotype Relations in Primary Familial Brain Calcification: Systematic MDSGene Review

Case Report: Two Novel Frameshift Mutations in SLC20A2 and One Novel Splice Donor Mutation in PDGFB Associated With Primary Familial Brain Calcification

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