Association of 4qA-Specific Distal D4Z4 Hypomethylation With Disease Severity and Progression in Facioscapulohumeral Muscular Dystrophy

Zheng, Fuze; Qiu, Liangliang; Chen, Long; Zheng, Ying; Lin, Xiaodan; He, Junjie; Lin, Xiao; He, Qifang; Lin, Yu-Hua; Lin, Lin; Wang, Lili; Lin, Feng; Yang, Kang; Lin, Min; Lin, Yi Wen; Fu, Ying; Wang, Ning; Wang, Zhiqiang

doi:10.1212/wnl.0000000000207418

Cited by 9 publications

(6 citation statements)

References 26 publications

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“…The methylation analysis in patients carrying SMCHD1 variants revealed a marked hypomethylation consistent with FSHD, especially at the level of the DR1 region ( Table 3 ). This finding is consistent with previous studies ( Hartwerk et al, 2013 ; Huichalaf et al, 2014 ; Caputo et al, 2022b ; Hiramuki et al, 2022 ; Zheng et al, 2023 ). The striking DR1 hypomethylation supported a functional effect for the identified SMCHD1 variants, even for those detected in patients carrying a short DRA (in the FSHD1 range).…”

Section: Discussionsupporting

confidence: 94%

Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD

Strafella,

Caputo,

Bortolani

et al. 2023

Front. Genet.

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Introduction: Despite the progress made in the study of Facioscapulohumeral Dystrophy (FSHD), the wide heterogeneity of disease complicates its diagnosis and the genotype-phenotype correlation among patients and within families. In this context, the present work employed Whole Exome Sequencing (WES) to investigate known and unknown genetic contributors that may be involved in FSHD and may represent potential disease modifiers, even in presence of a D4Z4 Reduced Allele (DRA).Methods: A cohort of 126 patients with clinical signs of FSHD were included in the study, which were characterized by D4Z4 sizing, methylation analysis and WES. Specific protocols were employed for D4Z4 sizing and methylation analysis, whereas the Illumina® Next-Seq 550 system was utilized for WES. The study included both patients with a DRA compatible with FSHD diagnosis and patients with longer D4Z4 alleles. In case of patients harboring relevant variants from WES, the molecular analysis was extended to the family members.Results: The WES data analysis highlighted 20 relevant variants, among which 14 were located in known genetic modifiers (SMCHD1, DNMT3B and LRIF1) and 6 in candidate genes (CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1). Most of them were found together with a permissive short (4–7 RU) or borderline/long DRA (8–20 RU), supporting the possibility that different genes can contribute to disease heterogeneity in presence of a FSHD permissive background. The segregation and methylation analysis among family members, together with clinical findings, provided a more comprehensive picture of patients.Discussion: Our results support FSHD pathomechanism being complex with a multigenic contribution by several known (SMCHD1, DNMT3B, LRIF1) and possibly other candidate genes (CTCF, DNMT1, DNMT3A, EZH2, SUV39H1) to disease penetrance and expressivity. Our results further emphasize the importance of extending the analysis of molecular findings within the proband’s family, with the purpose of providing a broader framework for understanding single cases and allowing finer genotype-phenotype correlations in FSHD-affected families.

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Section: Discussionsupporting

confidence: 94%

Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD

Strafella,

Caputo,

Bortolani

et al. 2023

Front. Genet.

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“…The methylation analysis in patients carrying SMCHD1 variants revealed a marked hypomethylation consistent with FSHD, especially at the level of the DR1 region (Table 3). This finding is consistent with previous studies (Hartwerk et al, 2013;Huichalaf et al, 2014;Caputo et al, 2022b;Hiramuki et al, 2022;Zheng et al, 2023). The striking DR1 hypomethylation supported a functional effect for the identified SMCHD1 variants, even for those detected in patients carrying a short DRA (in the FSHD1 range).…”

Section: Discussionsupporting

confidence: 92%

Insights in Genetics of Common and Rare Diseases: 2022

2024

Frontiers Research Topics

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Frontiers is more than just an open access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. Frontiers journal seriesThe Frontiers journal series is a multi-tier and interdisciplinary set of openaccess, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. All Frontiers journals are driven by researchers for researchers; therefore, they constitute a service to the scholarly community. At the same time, the Frontiers journal series operates on a revolutionary invention, the tiered publishing system, initially addressing specific communities of scholars, and gradually climbing up to broader public understanding, thus serving the interests of the lay society, too. Dedication to qualityEach Frontiers article is a landmark of the highest quality, thanks to genuinely collaborative interactions between authors and review editors, who include some of the world's best academicians. Research must be certified by peers before entering a stream of knowledge that may eventually reach the public -and shape society; therefore, Frontiers only applies the most rigorous and unbiased reviews. Frontiers revolutionizes research publishing by freely delivering the most outstanding research, evaluated with no bias from both the academic and social point of view. By applying the most advanced information technologies, Frontiers is catapulting scholarly publishing into a new generation. What are Frontiers Research Topics?Frontiers Research Topics are very popular trademarks of the Frontiers journals series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area.

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“…However, we observed that the clinical severity of the compound heterozygote proband carrying a paternally inherited D4Z4 allele (eight repeat units) and a maternally inherited D4Z4 allele (four repeat units) was milder than that of her younger brother, who carried a single D4Z4 allele with four repeat units from his mother. Methylation analysis showed that the compound heterozygous sister had a higher methylation level of CpG6 than the heterozygous brother, which is consistent with the conclusion of previous studies that, besides the size of the D4Z4 repeats, the level of CpG6 methylation can be used as an indicator of the severity of the disease (27).…”

Section: Discussionsupporting

confidence: 91%

Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping

Jiang,

Cai,

et al. 2024

Front. Neurol.

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ObjectiveFacioscapulohumeral muscular dystrophy type 1 (FSHD1) is one of the most common forms of autosomal-dominant muscular dystrophies characterized by variable disease penetrance due to shortened D4Z4 repeat units on 4q35. The molecular diagnosis of FSHD1 is usually made by Southern blotting, which is complex, time-consuming, and lacks clinical practicality. Therefore, in this study, optical genome mapping (OGM) is employed for the genetic diagnosis of FSHD1. Furthermore, epigenetic heterogeneity is determined from methylation analysis.MethodsGenomic DNA samples from four members of the same family were subjected to whole-exome sequencing. OGM was used to identify structural variations in D4Z4, while sodium bisulfite sequencing helped identify the methylation levels of CpG sites in a region located distally to the D4Z4 array. A multidisciplinary team collected the clinical data, and comprehensive family analyses aided in the assessment of phenotypes and genotypes.ResultsWhole-exome sequencing did not reveal variants related to clinical phenotypes in the patients. OGM showed that the proband was a compound heterozygote for the 4qA allele with four and eight D4Z4 repeat units, whereas the affected younger brother had only one 4qA allele with four D4Z4 repeat units. Both the proband and her younger brother were found to display asymmetric weakness predominantly involving the facial, shoulder girdle, and upper arm muscles, whereas the younger brother had more severe clinical symptoms. The proband's father, who was found to be normal after a neurological examination, also carried the 4qA allele with eight D4Z4 repeat units. The unaffected mother exhibited 49 D4Z4 repeat units of the 4qA allele and a minor mosaic pattern with four D4Z4 repeat units of the 4qA allele. Consequently, the presence of the 4qA allele in the four D4Z4 repeat units strongly pointed to the occurrence of maternal germline mosaicism. The CpG6 methylation levels were lower in symptomatic patients compared to those in the asymptomatic parents. The older sister had lower clinical scores and ACSS and higher CpG6 methylation levels than that of her younger brother.ConclusionsIn this study, two siblings with FSHD1 with phenotypically normal parents were identified by OGM. Our findings suggest that the 4qA allele of four D4Z4 repeats was inherited through maternal germline mosaicism. The clinical phenotype heterogeneity is influenced by the CpG6 methylation levels. The results of this study greatly aid in the molecular diagnosis of FSHD1 and in also understanding the clinical phenotypic variability underlying the disease.

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Association of 4qA-Specific Distal D4Z4 Hypomethylation With Disease Severity and Progression in Facioscapulohumeral Muscular Dystrophy

Cited by 9 publications

References 26 publications

Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD

Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD

Insights in Genetics of Common and Rare Diseases: 2022

Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping

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