Monosomy 18p is a risk factor for facioscapulohumeral dystrophy

Background: Patients with rare diseases face unique challenges in obtaining a diagnosis, appropriate medical care and access to support services. Whole genome and exome sequencing have increased identification of causal variants compared to single gene testing alone, with diagnostic rates of approximately 50% for inherited diseases, however integrated multi-omic analysis may further increase diagnostic yield. Additionally, multi-omic analysis can aid the explanation of genotypic and phenotypic heterogeneity, which may not be evident from single omic analyses. Main body: This scoping review took a systematic approach to comprehensively search the electronic databases MEDLINE, EMBASE, PubMed, Web of Science, Scopus, Google Scholar, and the grey literature databases OpenGrey / GreyLit for journal articles pertaining to multi-omics and rare disease, written in English and published prior to the 30th December 2018. Additionally, The Cancer Genome Atlas publications were searched for relevant studies and forward citation searching / screening of reference lists was performed to identify further eligible articles. Following title, abstract and full text screening, 66 articles were found to be eligible for inclusion in this review. Of these 42 (64%) were studies of multi-omics and rare cancer, two (3%) were studies of multi-omics and a pre-cancerous condition, and 22 (33.3%) were studies of non-cancerous rare diseases. The average age of participants (where known) across studies was 39.4 years. There has been a significant increase in the number of multi-omic studies in recent years, with 66.7% of included studies conducted since 2016 and 33% since 2018. Fourteen combinations of multi-omic analyses for rare disease research were returned spanning genomics, epigenomics, transcriptomics, proteomics, phenomics and metabolomics. Conclusions: This scoping review emphasises the value of multi-omic analysis for rare disease research in several ways compared to single omic analysis, ranging from the provision of a diagnosis, identification of prognostic biomarkers, distinct molecular subtypes (particularly for rare cancers), and identification of novel therapeutic targets. Moving forward there is a critical need for collaboration of multi-omic rare disease studies to increase the potential to generate robust outcomes and development of standardised biorepository collection and reporting structures for multi-omic studies.

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“…Monosomy 18p 1 / 50,0000 live births [113] • Investigation of the role of monosomy 18p on FSHD r type 2 development [114].…”

Section: Triglyceride Deposit Cardiomyovasculopathy Unknownmentioning

confidence: 99%

A scoping review and proposed workflow for multi-omic rare disease research

Kerr¹,

McAneney²,

Smyth³

et al. 2020

Orphanet J Rare Dis

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“…These 18p− patients with SMCHD1 among the deleted genes were found to have reduced D4Z4 repressive chromatin marks and express DUX4 in myonuclei when a permissive 4qA allele is present . Although these patients present a wide range of unrelated symptoms, FSHD clinical features were also detected in a few cases, demonstrating that the loss of one copy of SMCHD1 can cause FSHD2 . Furthermore, when FSHD2 patients have more than one permissive 4qA allele of appropriate size (ie, 1‐8 units in FSHD1, <20 in FSHD2), biallelic expression of DUX4 can occur, which can result in a higher susceptibility to disease presentation and could potentially cause a more severe FSHD phenotype …”

Section: D4z4 Chromatin Structure and The Role Of Smchd1mentioning

confidence: 99%

“…SMCHD1 loss‐of‐function mutations such as mutations causing frameshifts and premature stop codons or aberrant splicing are well‐described causes of FSHD2 . Recent studies have also highlighted that the loss of one copy of the SMCHD1 gene can occur through chromosome 18p microdeletions, or the complete loss of the short arm of chromosome 18 in 18p deletion syndrome (18p−) . These 18p− patients with SMCHD1 among the deleted genes were found to have reduced D4Z4 repressive chromatin marks and express DUX4 in myonuclei when a permissive 4qA allele is present .…”

Section: D4z4 Chromatin Structure and The Role Of Smchd1mentioning

confidence: 99%

“…Recent studies have also highlighted that the loss of one copy of the SMCHD1 gene can occur through chromosome 18p microdeletions, or the complete loss of the short arm of chromosome 18 in 18p deletion syndrome (18p−) . These 18p− patients with SMCHD1 among the deleted genes were found to have reduced D4Z4 repressive chromatin marks and express DUX4 in myonuclei when a permissive 4qA allele is present . Although these patients present a wide range of unrelated symptoms, FSHD clinical features were also detected in a few cases, demonstrating that the loss of one copy of SMCHD1 can cause FSHD2 .…”

Section: D4z4 Chromatin Structure and The Role Of Smchd1mentioning

confidence: 99%

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Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy

et al. 2020

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Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (FSHD1) or by mutations in D4Z4 chromatin modifiers such as Structural Maintenance of Chromosomes Hinge Domain Containing 1 (FSHD2). These two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the D4Z4 repeat. All together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the DUX4 gene, which is otherwise kept epigenetically silent in skeletal muscle. DUX4 is consistently transcriptionally upregulated in FSHD1 and FSHD2 skeletal muscle cells where it is believed to exercise a toxic effect. Here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of FSHD, with a focus on one of the consequences that these epigenetic changes inflict, the DUX4-induced immune deregulation cascade. Moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the FSHD locus. K E Y W O R D S

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“…Moreover, D4Z4 hypomethylation, in the presence of the haplotype 4qA/PAS distal to the D4Z4 array, which is considered permissive of DUX4 expression, is not associated with a muscle phenotype in patients with Bosma Arhinia and Microphthalmia syndrome (BAMS), patients affected with ICF (Immunodeficiency, Centromeric Instability, and Facial anomalies) homozygotes for DNMT3B mutation and their heterozygote parents [78], or patients carrying a deletion of the 18p chromosome containing the SMCHD1 gene [79]. Besides, in the few families with FSHD index cases carrying a mutation in DNMT3B [47] or an 18p deletion [80], the presence of a DNA mutation and D4Z4 hypomethylation does not segregate with clinical signs of the disease. Furthermore, as highlighted by molecular combing [81], a significant proportion of individuals affected by FSHD display an atypical genotype, with complex distal rearrangements [82], presence of proximal deletions, additional 10q alleles, in the absence of D4Z4 array shortening, SMCHD1 variants, or D4Z4 hypomethylation [83].…”

Section: Dna Methylation In Fshd2mentioning

confidence: 99%

Does DNA Methylation Matter in FSHD?

Salsi

Magdinier

Tupler

2020

Genes

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Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 hypomethylation is a consequence of the chromatin structure present in the contracted allele, rather than a proxy of its function. Besides, CpG methylation at D4Z4 DNA is reduced in patients presenting diseases unrelated to muscle progressive wasting, like Bosma Arhinia and Microphthalmia syndrome, a developmental disorder, as well as ICF syndrome. Consistent with these observations, the analysis of epigenetic reprogramming at the D4Z4 locus in human embryonic and induced pluripotent stem cells indicate that other mechanisms, independent from the repeat number, are involved in the control of the epigenetic structure at D4Z4.

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Monosomy 18p is a risk factor for facioscapulohumeral dystrophy

Cited by 15 publications

References 28 publications

A scoping review and proposed workflow for multi-omic rare disease research

A scoping review and proposed workflow for multi-omic rare disease research

Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy

Does DNA Methylation Matter in FSHD?

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