Cross-sectional Neuromuscular Phenotyping Study of Patients With Arhinia With SMCHD1 Variants
Payam MohasselNing ChangKaoru InoueAngela DelaneyYing HuSandra DonkervoortDimah SaadeBridgette Jeanne BilliouxBrooke MeaderRita VolochayevChamindra G. KonersmanAngela M. KaindlChie Hee ChoBianca RussellAdrián RodríguezKamala FosterA. Reghan FoleySteven A. MoorePeter L. JonesCarsten G. BönnemannTakako I. JonesNatalie D. Shaw
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Abstract:
Facioscapulohumeral muscular dystrophy type 2 (FSHD2) and arhinia are 2 distinct disorders caused by pathogenic variants in the same gene: SMCHD1. The mechanism underlying this phenotypic divergence remains unclear. In this study, we characterize the neuromuscular phenotype of individuals with arhinia caused by SMCHD1 variants and analyze their complex genetic and epigenetic criteria to assess their risk for FSHD2.Eleven individuals with congenital nasal anomalies, including arhinia, nasal hypoplasia, or anosmia, underwent a neuromuscular examination, genetic testing, muscle ultrasound, and muscle MRI. Risk for FSHD2 was determined by combined genetic and epigenetic analysis of 4q35 haplotype, D4Z4 repeat length, and methylation profile. We also compared expression levels of pathogenic DUX4 mRNA in primary myoblasts or dermal fibroblasts (upon myogenic differentiation or epigenetic transdifferentiation, respectively) in these individuals vs those with confirmed FSHD2.Among the 11 individuals with rare, pathogenic, heterozygous missense variants in exons 3-11 of SMCHD1, only a subset (n = 3/11; 1 male, 2 female; age 25-51 years) met the strict genetic and epigenetic criteria for FSHD2 (D4Z4 repeat unit length <21 in cis with a 4qA haplotype and D4Z4 methylation <30%). None of the 3 individuals had typical clinical manifestations or muscle imaging findings consistent with FSHD2. However, the patients with arhinia meeting the permissive genetic and epigenetic criteria for FSHD2 displayed some DUX4 expression in dermal fibroblasts under the epigenetic de-repression by drug treatment and in the primary myoblasts undergoing myogenic differentiation.In this cross-sectional study, we identified patients with arhinia who meet the full genetic and epigenetic criteria for FSHD2 and display the molecular hallmark of FSHD-DUX4 de-repression and expression in vitro-but who do not manifest with the typical clinicopathologic phenotype of FSHD2. The distinct dichotomy between FSHD2 and arhinia phenotypes despite an otherwise poised DUX4 locus implies the presence of novel disease-modifying factors that seem to operate as a switch, resulting in one phenotype and not the other. Identification and further understanding of these disease-modifying factors will provide valuable insight with therapeutic implications for both diseases.Keywords:
Facioscapulohumeral muscular dystrophy
Muscle disorder
Muscular dystrophies are a group of disorders that cause progressive muscle weakness. There is an increasing interest for the development of biomarkers for these disorders and specifically for Duchene Muscular Dystrophy. Limited research however, has been performed on the biomarkers' development for the most rare muscular dystrophies, like the Facioscapulohumeral Muscular Dystrophy, Limb-Girdle Muscular Dystrophy and Myotonic Dystrophy type 2. Here, we aimed to identify novel serum-based miRNA biomarkers for these rare muscular dystrophies, through high-throughput next-generation RNA sequencing. We identified many miRNAs that associate with muscular dystrophy patients compared to controls. Based on a series of selection criteria, the two best candidate miRNAs for each of these disorders were chosen and validated in a larger number of patients. Our results showed that miR-223-3p and miR-206 are promising serum-based biomarkers for Facioscapulohumeral Muscular Dystrophy type 1, miR-143-3p and miR-486-3p for Limb-Girdle Muscular Dystrophy type 2A whereas miR-363-3p and miR-25-3p associate with Myotonic Dystrophy type 2. Some of the identified miRNAs were significantly elevated in the serum of the patients compared to controls, whereas some others were lower. In conclusion, we provide new evidence that certain circulating miRNAs may be used as biomarkers for three types of rare muscular dystrophies.
Facioscapulohumeral muscular dystrophy
Dysferlin
Muscle disorder
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Muscular dystrophies are a clinically and genetically heterogeneous group of inherited myogenic disorders. In clinical tests for these diseases, creatine kinase (CK) is generally used as diagnostic blood-based biomarker. However, because CK levels can be altered by various other factors, such as vigorous exercise, etc., false positive is observed. Therefore, three microRNAs (miRNAs), miR-1, miR-133a, and miR-206, were previously reported as alternative biomarkers for duchenne muscular dystrophy (DMD). However, no alternative biomarkers have been established for the other muscular dystrophies.We, therefore, evaluated whether these miR-1, miR-133a, and miR-206 can be used as powerful biomarkers using the serum from muscular dystrophy patients including DMD, myotonic dystrophy 1 (DM1), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), becker muscular dystrophy (BMD), and distal myopathy with rimmed vacuoles (DMRV) by qualitative polymerase chain reaction (PCR) amplification assay.Statistical analysis indicated that all these miRNA levels in serum represented no significant differences between all muscle disorders examined in this study and controls by Bonferroni correction. However, some of these indicated significant differences without correction for testing multiple diseases (P < 0.05). The median values of miR-1 levels in the serum of patients with LGMD, FSHD, and BMD were approximately 5.5, 3.3 and 1.7 compared to that in controls, 0.68, respectively. Similarly, those of miR-133a and miR-206 levels in the serum of BMD patients were about 2.5 and 2.1 compared to those in controls, 1.03 and 1.32, respectively.Taken together, our data demonstrate that levels of miR-1, miR-133a, and miR-206 in serum of BMD and miR-1 in sera of LGMD and FSHD patients showed no significant differences compared with those of controls by Bonferroni correction. However, the results might need increase in sample sizes to evaluate these three miRNAs as variable biomarkers.
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Epigenetics describes the study of cellular modifications that can modify the expression of genes without changing the DNA sequence. DNA methylation is one of the most stable and prevalent epigenetic mechanisms. Twin studies have been a valuable model for unraveling the genetic and epigenetic epidemiology of complex traits, and now offer a potential to dissect the factors that impact DNA methylation variability and its biomedical significance. The twin design specifically allows for the study of genetic, environmental and lifestyle factors, and their potential interactions, on epigenetic profiles. Furthermore, genetically identical twins offer a unique opportunity to assess nongenetic impacts on epigenetic profiles. Here, we summarize recent findings from twin studies of DNA methylation profiles across tissues, to define current knowledge regarding the genetic and nongenetic factors that influence epigenetic variation.
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TOBACCO AND DNA METHYLATION THE CASE FOR EPIGENETIC ALTERATIONS The mechanisms of the long-term impacts of exposure to chemical substances remain poorly understood. While genotoxic and mutagenic effects have been well characterized, epigenetic mechanisms such as DNA methylation could also account for the delayed effects of exposures. It is in the case of tobacco that the strongest arguments for a role of these mechanisms have been obtained in human populations. This text presents recent data on this issue demonstrating the plausibility of epigenetic mechanisms to explain the persistence of biological signals long after stopping exposure.
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BETWEEN the middle and the end of the 19th century, muscular dystrophies were established as clinical and pathological entities distinct from neurogenic muscular atrophies. However, keen eyes of excellent clinicians have never overlooked unusual signs occasionally observed in muscular dystrophy patients. Landouzy and Déjèrine1observed fasciculations in one of their patients with facioscapulohumeral (FSH) dystrophy and stated, "Fibrillary contractions of muscle favor myelopathy." Some cases of atypical muscular dystrophies with fasciculations have been described. As early as 1886 Penzoldt2recognized such a disease and considered it a transitional form between muscular dystrophy and spinal muscular atrophy. Erb3in 1910 emphasized the difficulty in diagnosing muscular dystrophy because of the presence of such a transitional form. However, little attention was paid such atypical muscular dystrophies. Recently, biochemical, electron microscopic, and electrophysiological studies have shown the presence of several new diseases, some of which are clinically difficult to differentiate
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Fasciculation
Congenital muscular dystrophy
Progressive muscular atrophy
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BETWEEN the middle and the end of the 19th century, muscular dystrophies were established as clinical and pathological entities distinct from neurogenic muscular atrophies. However, keen eyes of excellent clinicians have never overlooked unusual signs occasionally observed in muscular dystrophy patients. Landouzy and Déjèrine1observed fasciculations in one of their patients with facioscapulohumeral (FSH) dystrophy and stated, "Fibrillary contractions of muscle favor myelopathy." Some cases of atypical muscular dystrophies with fasciculations have been described. As early as 1886 Penzoldt2recognized such a disease and considered it a transitional form between muscular dystrophy and spinal muscular atrophy. Erb3in 1910 emphasized the difficulty in diagnosing muscular dystrophy because of the presence of such a transitional form. However, little attention was paid such atypical muscular dystrophies. Recently, biochemical, electron microscopic, and electrophysiological studies have shown the presence of several new diseases, some of which are clinically difficult to differentiate
Facioscapulohumeral muscular dystrophy
Fasciculation
Congenital muscular dystrophy
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Transient nutritional exposures during critical ontogenic periods can cause persistent changes in gene expression, metabolism, and risk of various diseases. We have been investigating whether such ‘developmental programming’ occurs via nutritional influences on developmental epigenetics. Our studies in agouti viable yellow and axin-fused mice showed that developmental establishment of DNA methylation at ‘metastable epialleles’ is especially sensitive to maternal nutritional status around the time of conception. At metastable epialleles, DNA methylation is established stochastically in the early embryo and subsequently maintained during differentiation of diverse lineages, resulting in systemic interindividual epigenetic variation that is not genetically mediated. Lately, using a multiple-tissue screen for interindividual variation in DNA methylation, we have identified human genomic regions that appear to be metastable epialleles. Stochastic establishment of DNA methylation at these loci is affected by maternal nutrition around the time of conception, consistent across multiple tissues, and stable for many years. Most recently, our studies using genome-wide bisulfite sequencing have identified candidate metastable epialleles that are associated with human disease, providing exciting opportunities for epigenetic epidemiology.
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