A biallelic mutation links<i>MYORG</i>to autosomal-recessive primary familial brain calcification

Forouhideh, Yalda; Müller, Kathrin; Ruf, Wolfgang; Assi, Muhannad; Şeker, Tuncay; Tunca, Ceren; Knehr, Antje; Strom, Tim M.; Gorges, Martin; Schradt, Falk; Meitinger, Thomas; Ludolph, Albert C.; Pinkhardt, Elmar H.; Başak, A. Nazlı; Kassubek, Jan; Uttner, Ingo; Weishaupt, Jochen H.

doi:10.1093/brain/awy343

Cited by 18 publications

(11 citation statements)

References 7 publications

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“…Our data suggest that the majority of cases have a disease onset in late adulthood with a combination of dysarthria, ataxia, parkinsonism, and cognitive decline consistent with the phenotypes previously reported in MYORG mutations 5,6,[16][17][18][19] and other autosomal dominant PFBC-causing genes. 20 However, parkinsonism with supranuclear gaze palsy was frequently observed (37.8% of cases) in our cohort and has not been previously described in MYORG mutation carriers.…”

Section: Discussionsupporting

confidence: 89%

MYORG -related disease is associated with central pontine calcifications and atypical parkinsonism

et al. 2020

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ObjectiveTo identify the phenotypic, neuroimaging, and genotype-phenotype expression of MYORG mutations.MethodsUsing next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in SLC20A2, PDGFRB, PDGBB, and XPR1. In-depth phenotyping and neuroimaging investigations were performed in all cases reported here.ResultsWe identified 12 distinct deleterious MYORG variants in 7 of the 60 families with PFBC. Overall, biallelic MYORG mutations accounted for 11.6% of PFBC families in our cohort. A heterogeneous phenotypic expression was identified within and between families with a median age at onset of 56.4 years, a variable combination of parkinsonism, cerebellar signs, and cognitive decline. Psychiatric disturbances were not a prominent feature. Cognitive assessment showed impaired cognitive function in 62.5% of cases. Parkinsonism associated with vertical nuclear gaze palsy was the initial clinical presentation in 1/3 of cases and was associated with central pontine calcifications. Cerebral cortical atrophy was present in 37% of cases.ConclusionsThis large, multicentric study shows that biallelic MYORG mutations represent a significant proportion of autosomal recessive PFBC. We recommend screening MYORG mutations in all patients with primary brain calcifications and autosomal recessive or negative family history, especially when presenting clinically as atypical parkinsonism and with pontine calcification on brain CT.

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Section: Discussionsupporting

confidence: 89%

MYORG -related disease is associated with central pontine calcifications and atypical parkinsonism

et al. 2020

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“…In addition to our cohort, 44 heterozygous carriers have been reported on in seven other studies (Supporting information Table S4). 7,[9][10][11][12][13]15 Among them, 33 heterozygous carriers from six of these studies had CT scans available. Penetrance of imaging phenotype was 0 of 17 (0%), 1 of 1 (100%), 0 of 1 (0%), 3 of 5 (60%), 3 of 4 (75%), and 0 of 5 (0%), respectively.…”

Section: Discussionmentioning

confidence: 99%

“…7 To date, biallelic mutations have been identified in 28 unrelated families. [7][8][9][10][11][12][13][14][15] Interestingly, 7 heterozygous carriers from five of these families also exhibited brain calcifications of diverse severity. 10,12,13 More studies are warranted to investigate whether this is a common phenomenon and whether MYORG mutation heterozygosity is a contributing factor to brain calcifications.…”

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MYORG Mutation Heterozygosity Is Associated With Brain Calcification

et al. 2020

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A BS TRACT: Background: Biallelic mutations in the MYORG gene were first identified as the cause of recessively inherited primary familial brain calcification. Interestingly, some heterozygous carriers also exhibited brain calcifications.Objectives: To further investigate the role of single heterozygous MYORG mutations in the development of brain calcifications. Methods: A nation-wide cohort of Chinese primary familial brain calcification probands was enrolled from March 2016 ---

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“…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: 94%

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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A biallelic mutation linksMYORGto autosomal-recessive primary familial brain calcification

Cited by 18 publications

References 7 publications

MYORG -related disease is associated with central pontine calcifications and atypical parkinsonism

MYORG -related disease is associated with central pontine calcifications and atypical parkinsonism

MYORG Mutation Heterozygosity Is Associated With Brain Calcification

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

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