Primary familial brain calcification caused by a novel homozygous MYORG mutation in a consanguineous Italian family

Ramos, Eliana Marisa; Roca, Alessandro; Chumchim, Noravit; Dokuru, Deepika; Berlo, Victoria Van; Michele, G. De; Lieto, Maria; Tedeschi, Enrico; Coppola, Giovanni

doi:10.1007/s10048-019-00571-8

Cited by 22 publications

(29 citation statements)

References 17 publications

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“…However, brain calcifications in some heterozygous MYORG carriers have recently been observed. In five families reported on in the literature and seven families in our cohort with biallelic MYORG mutation carriers, a total of 19 family members with heterozygous mutations also exhibited brain calcifications of varying severity, from mild calcifications limited to the basal ganglia that were hard to differentiate from physiological calcifications to diffuse and moderate calcium deposits that highlighted the role of single heterozygous mutations in the development of brain calcifications. Moreover, single heterozygous mutations were identified in 9 probands and 7 of their affected family members, 4 of which were previously reported on in patients with biallelic mutations, either in the homozygous or compound heterozygous state.…”

Section: Discussionmentioning

confidence: 74%

“…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%

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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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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

MYORG Mutation Heterozygosity Is Associated With Brain Calcification

et al. 2020

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“…Very recently, mutations in the Myogenic Regulating Glycosylase (MYORG) gene were identified as a novel genetic cause for autosomal-recessive PFBC in Chinese patients [51, 52]. MYORG gene encodes a glycosyl hydrolase involved in myogenesis and expressed throughout the brain, particularly in the cerebellum, but its role in the pathogenesis of PFBC is yet unknown [53].…”

Section: Classificationmentioning

confidence: 99%

Basal ganglia calcifications (Fahr’s syndrome): related conditions and clinical features

et al. 2019

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Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms associated with bilateral basal ganglia calcifications (which could occur in other peculiar brain structures, such as dentate nuclei) identifies a clinical picture defined as Fahr's Disease. This denomination mainly refers to idiopathic forms in which no metabolic or other underlying causes are identified. Recently, mutations in four different genes (SLC20A2, PDGFRB, PDGFB, and XPR1) were identified, together with novel mutations in the Myogenic Regulating Glycosylase gene, causing the occurrence of movement disorders, cognitive decline, and psychiatric symptoms. On the other hand, secondary forms, also identified as Fahr's syndrome, have been associated with different conditions: endocrine abnormalities of PTH, such as hypoparathyroidism, other genetically determined conditions, brain infections, or toxic exposure. The underlying pathophysiology seems to be related to an abnormal calcium/phosphorus homeostasis and transportation and alteration of the blood-brain barrier.

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“…It has been argued that autozygosity-driven WES analysis is most powerful in populations of GME countries where the identification of genes underlying autosomal recessive diseases is facilitated by high population inbreeding rate and large family size . Nonetheless, reports of genetic diagnoses and novel disease-gene associations in Italian consanguineous families are not uncommon in the literature (see Spataro et al, 2019;Ramos et al, 2019;Milev et al, 2018 as illustrative recent papers). We aimed to investigate whether autozygosity-driven WES analysis could be as effective in a country like Italy where population inbreeding rate is lower and family size is on average smaller than in GME countries.…”

Section: Introductionmentioning

confidence: 99%

Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East

et al. 2020

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Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low.Nonetheless, consanguineous Italian families are not uncommon in publications of genetic findings and are often key to new associations of genes with rare diseases. We collected 52 patients from 47 consanguineous families with suspected recessive diseases, 29 originated in GME countries and 18 of Italian descent. We performed autozygosity-driven exome analysis by detecting long runs of homozygosity (ROHs>1.5 Mb) and by prioritizing candidate clinical variants within. We identified a pathogenic synonymous variant that had been previously missed in NARS2 and we increased an initial high diagnostic rate (47%) to 55% by matchmaking our candidate genes and including in the analysis shorter ROHs that may also happen to be autozygous. GME and Italian families contributed to diagnostic yield comparably. We found no significant difference either in the extension of the autozygous genome, or in the distribution of candidate clinical variants between GME and Italian families, while we showed that the average autozygous genome was larger and the mean number of candidate clinical variants was significantly higher (p=0.003) in mutation-positive than in mutationnegative individuals, suggesting that these features influence the likelihood that the disease is autozygosity-related. We highlight the utility of autozygosity-driven genomic analysis also in countries and/or communities where consanguinity is not widespread cultural tradition.Patients. This study includes 47 families referred in years 2012-2017 to the Medical Genetics Unit,

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Primary familial brain calcification caused by a novel homozygous MYORG mutation in a consanguineous Italian family

Cited by 22 publications

References 17 publications

MYORG Mutation Heterozygosity Is Associated With Brain Calcification

MYORG Mutation Heterozygosity Is Associated With Brain Calcification

Basal ganglia calcifications (Fahr’s syndrome): related conditions and clinical features

Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East

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