Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.
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SUBMITTER: Lemmers RJ
PROVIDER: S-EPMC3671095 | biostudies-literature | 2012 Dec
REPOSITORIES: biostudies-literature
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Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.
Lemmers Richard J L F RJ Tawil Rabi R Petek Lisa M LM Balog Judit J Block Gregory J GJ Santen Gijs W E GW Amell Amanda M AM van der Vliet Patrick J PJ Almomani Rowida R Straasheijm Kirsten R KR Krom Yvonne D YD Klooster Rinse R Sun Yu Y den Dunnen Johan T JT Helmer Quinta Q Donlin-Smith Colleen M CM Padberg George W GW van Engelen Baziel G M BG de Greef Jessica C JC Aartsma-Rus Annemieke M AM Frants Rune R RR de Visser Marianne M Desnuelle Claude C Sacconi Sabrina S Filippova Galina N GN Bakker Bert B Bamshad Michael J MJ Tapscott Stephen J SJ Miller Daniel G DG van der Maarel Silvère M SM
Nature genetics 20121111 12
Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain c ...[more]
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Project description:ImportanceFacioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disorder, associated with the deletion of tandemly arrayed D4Z4 repetitive elements. The extensive use of molecular analysis of the D4Z4 locus for FSHD diagnosis has revealed wide clinical variability, suggesting that subgroups of patients exist among carriers of the D4Z4 reduced allele (DRA).ObjectiveTo investigate the clinical expression of FSHD in the genetic subgroup of carriers of a DRA with 7 to 8 repeat units (RUs).Design, setting, and participantsThis multicenter cross-sectional study included 422 carriers of DRA with 7 to 8 RUs (187 unrelated probands and 235 relatives) from a consecutive sample of 280 probands and 306 relatives from the Italian National Registry for FSHD collected between 2008 and 2016. Participants were evaluated by the Italian Clinical Network for FSHD, and all clinical and molecular data were collected in the Italian National Registry for FSHD database. Data analysis was conducted from January 2017 to June 2018.Main outcomes and measuresThe phenotypic classification of probands and relatives was obtained by applying the Comprehensive Clinical Evaluation Form which classifies patients in the 4 following categories: (1) participants presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) participants with muscle weakness limited to scapular girdle or facial muscles (category B, subcategories B1 and B2), (3) asymptomatic or healthy participants (category C, subcategories C1 and C2), and (4) participants with myopathic phenotypes presenting clinical features not consistent with FSHD canonical phenotype (category D, subcategories D1 and D2).ResultsA total of 187 probands (mean [SD] age at last neurological examination, 53.5 [15.2] years; 103 [55.1%] men) and 235 relatives (mean [SD] age at last neurologic examination, 45.1 [17.0] years; 104 [44.7%] men) with a DRA with 7 to 8 RUs and a molecular diagnosis of FSHD were evaluated. Of 187 probands, 99 (52.9%; 95% CI, 45.7%-60.1%) displayed the classic FSHD phenotype, whereas 86 (47.1%; 95% CI, 39.8%-54.3%) presented incomplete or atypical phenotypes. Of 235 carrier relatives from 106 unrelated families, 124 (52.8%; 95% CI, 46.4%-59.7%) had no motor impairment, whereas a small number (38 [16.2%; 95% CI, 9.8%-23.1%]) displayed the classic FSHD phenotype, and 73 (31.0%; 95% CI, 24.7%-38.0%) presented with incomplete or atypical phenotypes. In 37 of 106 families (34.9%; 95% CI, 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, while only 20 families (18.9%; 95% CI, 11.9%-27.6%) had a member with autosomal dominant FSHD.Conclusions and relevanceThis study found large phenotypic variability associated with individuals carrying a DRA with 7 to 8 RUs, in contrast to the indication that a positive molecular test is the only determining aspect for FSHD diagnosis. These findings suggest that carriers of a DRA with 7 to 8 RUs constitute a genetic subgroup different from classic FSHD. Based on these results, it is recommended that clinicians use the Comprehensive Clinical Evaluation Form for clinical classification and, whenever possible, study the extended family to provide the most adequate clinical management and genetic counseling.
| S-EPMC7195625 | biostudies-literature
Project description:PurposeFacioscapulohumeral muscular dystrophy (FSHD) is a common adult muscular dystrophy. Over 95% of FSHD cases are associated with contraction of the D4Z4 tandem repeat (~3.3 kb per unit) at 4q35 with a specific genomic configuration (haplotype) called 4qA. Molecular diagnosis of FSHD typically requires pulsed-field gel electrophoresis with Southern blotting. We aim to develop novel genomic and computational methods for characterising D4Z4 repeat numbers in FSHD.MethodsWe leveraged a single-molecule optical mapping platform that maps locations of restriction enzyme sites on high molecular weight (>150 kb) DNA molecules. We developed bioinformatics methods to address several challenges, including the differentiation of 4qA with 4qB alleles, the differentiation of 4q35 and 10q26 segmental duplications, the quantification of repeat numbers with different enzymes that may or may not have recognition sites within D4Z4 repeats. We evaluated the method on 25 human subjects (13 patients, 3 individual control subjects, 9 control subjects from 3 families) labelled by the Nb.BssSI and/or Nt.BspQI enzymes.ResultsWe demonstrated that the method gave a direct quantitative measurement of repeat numbers on D4Z4 repeats with 4qA allelic configuration and the levels of postzygotic mosaicism. Our method had high concordance with Southern blots from several cohorts on two platforms (Bionano Saphyr and Bionano Irys), but with improved quantification of repeat numbers.ConclusionWhile the study is limited by small sample size, our results demonstrated that single-molecule optical mapping is a viable approach for more refined analysis on genotype-phenotype relationships in FSHD, especially when postzygotic mosaicism is present.
| S-EPMC7029236 | biostudies-literature
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder which is typically transmitted by an autosomal dominant pattern, although reduced penetrance and sporadic cases caused by de novo mutations, are often observed. FSHD may be caused by a contraction of a repetitive element, located on chromosome 4 (4q35). This locus is named D4Z4 and consists of 11 to more than 100 repeated units (RU). The D4Z4 is normally hypermethylated and the genes located on this locus are silenced. In case of FSHD, the D4Z4 region is characterized by 1-10 repeats and results in the region being hypomethylated. However, 5% of FSHD cases do not carry the short allele of D4Z4 region. To date, two forms of FSHD (FSHD1 and FSHD2) are known. FSHD2 is usually observed in patients without the D4Z4 fragment contraction and carrying variants in SMCHD1 (18p11.32) gene. We report the case of a young adult patient who shows severe symptoms of FSHD. Preliminary genetic analysis did not clarify the phenotype, therefore we decided to study the family members by genetic and epigenetic approaches. The analysis of D4Z4 fragment resulted to be 8 RU in the affected proband and in his father; 26 RU in the mother and 25 RU in the maternal uncle. SMCHD1 analysis revealed a heterozygous variation within the exon 41. The variant was detected in the proband, her mother and the uncle. Furthermore, epigenetic analysis of CpG6 methylation regions showed significant hypomethylation in the affected patient (54%) and in the mother (56%), in contrast to the father (88%) and the uncle (81%) carrying higher methylation levels. The analysis of DR1 methylation levels reported hypomethylation for the proband (19%), the mother (11%), and the uncle (16%). The father showed normal DR1 methylation levels (>30%). Given these results, the combined inheritance of SMCHD1 variant and the short fragment might explain the severe FSHD phenotype displayed by the proband. On this subject, SMCHD1 analysis should be promoted in a larger number of patients, even in presence of D4Z4 contractions, to facilitate the genotype-phenotype correlation as well as, to enable a more precise diagnosis and prognosis of the disease.
| S-EPMC6279899 | biostudies-literature
Project description:A depth-ranging sensor (Kinect) based upper extremity motion analysis system was applied to determine the spectrum of reachable workspace encountered in facioscapulohumeral muscular dystrophy (FSHD).Reachable workspaces were obtained from 22 individuals with FSHD and 24 age- and height-matched healthy controls. To allow comparison, total and quadrant reachable workspace relative surface areas (RSAs) were obtained by normalizing the acquired reachable workspace by each individual's arm length.Significantly contracted reachable workspace and reduced RSAs were noted for the FSHD cohort compared with controls (0.473?±?0.188 vs. 0.747?±?0.082; P?<?0.0001). With worsening upper extremity function as categorized by the FSHD evaluation subscale II?+?III, the upper quadrant RSAs decreased progressively, while the lower quadrant RSAs were relatively preserved. There were no side-to-side differences in reachable workspace based on hand-dominance.This study demonstrates the feasibility and potential of using an innovative Kinect-based reachable workspace outcome measure in FSHD.
| S-EPMC4233016 | biostudies-literature
Project description:Facioscapulohumeral muscular dystrophy is the third most commonly found type of muscular dystrophy. The aim of this study was to correlate the D4Z4 repeat array fragment size to the orofacial muscle weakening exhibited in a group of patients with a genetically supported diagnosis of FSHD. Molecular genetic analysis was performed for 52 patients (27 female and 25 male) from a group that consisted of 36 patients with autosomal dominant pedigrees and 16 patients with either sporadic or unknown family status. The patients were tested with the southern blotting technique, using EcoRI/Avrll double digestion, and fragments were detected by a p13E-11 telomeric probe. Spearman's correlation was used to compare the fragment size with the degree of muscle weakening found in the forehead, periocular and perioral muscles. A positive non-significant correlation between the DNA fragment size and severity of muscle weakness was found for the forehead (r = 0.27; p = 0187), the periocular (r = 0.24; p = 0.232) and the left and right perioral (r = 0.29; p = 0.122), (r = 0.32; p = 0.085) muscles. Although FSHD patients exhibited a decrease in muscular activity related to the forehead, perioral, and periocular muscles the genotype-phenotype associations confirmed a weak to moderate non-significant correlation between repeat size and the severity of muscle weakness. Orofacial muscle weakening and its association with a D4Z4 contraction alone may not have the significance to serve as a prognostic biomarker, due to the weak to moderate association. Further studies with larger sample sizes are needed to determine the degree of genetic involvement in the facial growth in FSHD patients.
| S-EPMC8774153 | biostudies-literature
Project description:ObjectiveTo determine the frequency and relative importance of the most meaningful symptoms in facioscapulohumeral muscular dystrophy (FSHD) and to identify the demographic and clinical features that are associated with the greatest disease burden in this population.MethodsWe performed a cross-sectional study involving 328 participants with FSHD. Collectively, participants reported the prevalence and relative importance of 274 symptoms and 15 symptomatic themes. We assessed the association between symptomatic theme prevalence and participants' age, sex, disease duration, pain level, employment status, and education.ResultsParticipants answered >48,000 questions regarding their disease burden. The symptomatic themes with the highest prevalence in our sample were problems with shoulders or arms (96.9%), limitations with activities (94.7%), core weakness (93.8%), fatigue (93.8%), limitations with mobility and walking (93.6%), changed body image due to the disease (91.6%), and pain (87.7%). Problems with shoulders and arms and limitations with mobility and walking had the greatest effect on participants' lives. Employment status and the report of pain had the most extensive association with the prevalence of symptoms, with employment being associated with 8 of 15 of the symptomatic themes and pain being associated with 7 of 15 of the symptomatic themes. Men and women with FSHD experienced a similar prevalence of all symptomatic themes.ConclusionsAdults with FSHD experience a variety of symptoms that play an important role in their disease burden. These symptoms have a variable prevalence and importance in the FSHD population and are associated with disease duration, employment status, and pain level.
| S-EPMC6808532 | biostudies-literature
Project description:Facioscapulohumeral muscular dystrophy, known in genetic forms FSHD1 and FSHD2, is associated with D4Z4 repeat array chromatin relaxation and somatic derepression of DUX4 located in D4Z4. A complete copy of DUX4 is present on 4qA chromosomes, but not on the D4Z4-like repeats of chromosomes 4qB or 10. Normally, the D4Z4 repeat varies between 8 and 100 units, while in FSHD1 it is only 1-10 units. In the rare genetic form FSHD2, a combination of a 4qA allele with a D4Z4 repeat size of 8-20 units and heterozygous pathogenic variants in the chromatin modifier SMCHD1 causes DUX4 derepression and disease. In this study, we identified 11/79 (14%) FSHD2 patients with unusually large 4qA alleles of 21-70 D4Z4 units. By a combination of Southern blotting and molecular combing, we show that 8/11 (73%) of these unusually large 4qA alleles represent duplication alleles in which the long D4Z4 repeat arrays are followed by a small FSHD-sized D4Z4 repeat array duplication. We also show that these duplication alleles are associated with DUX4 expression. This duplication allele frequency is significantly higher than in controls (2.9%), FSHD1 patients (1.4%) and in FSHD2 patients with typical 4qA alleles of 8-20 D4Z4 units (1.5%). Segregation analysis shows that, similar to typical 8-20 units FSHD2 alleles, duplication alleles only cause FSHD in combination with a pathogenic variant in SMCHD1. We conclude that cis duplications of D4Z4 repeats explain DUX4 expression and disease presentation in FSHD2 families with unusual long D4Z4 repeats on 4qA chromosomes.
| S-EPMC6168970 | biostudies-literature
Project description:Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (? 8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1-3 repeats (1-3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1-3 DRA.Italy.66 index cases and 33 relatives carrying 1-3 DRA.The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk.No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1-3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment.The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity.
| S-EPMC4716236 | biostudies-literature
Project description:Facioscapulohumeral Muscular Dystrophy (FSHD): Wellstone Study
| PRJNA731943 | ENA
Project description:Background and objectivesFacioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient-reported Rasch-built interval scale on activity and participation for FSHD.MethodsA pre-phase FSHD-Rasch-built overall disability scale (pre-FSHD-RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease-related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2-4 weeks; reliability studies). The pre-FSHD-RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure.ResultsThe pre-FSHD-RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38-inquiry (originating from 32 items; six items split) FSHD-RODS was constructed achieving Rasch model expectations. Adequate test-retest reliability and (cross-cultural and external) validity scores were obtained.ConclusionsThe FSHD-RODS is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD.
| S-EPMC8251612 | biostudies-literature