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Background: 18p deletion syndrome is a rare disorder caused by partial or full monosomy of the short arm of chromosome 18. Clinical symptoms caused by 18p hemizygosity include cognitive impairment, mild facial dysmorphism, strabismus and ptosis. Among other genes, structural maintenance of chromosomes flexible hinge domain containing 1 ( SMCHD1 ) is hemizygous in most patients with 18p deletions. Digenic inheritance of a SMCHD1 mutation and a moderately sized D4Z4 repeat on a facioscapulohumeral muscular dystrophy (FSHD) permissive genetic background of chromosome 4 can cause FSHD type 2 (FSHD2)., Objectives: Since 12% of Caucasian individuals harbour moderately sized D4Z4 repeats on an FSHD permissive background, we tested if people with 18p deletions are at risk of developing FSHD., Methods: To test our hypothesis we studied different cellular systems originating from individuals with 18p deletions not presenting FSHD2 phenotype for transcriptional and epigenetic characteristics of FSHD at D4Z4. Furthermore, individuals with an idiopathic muscle phenotype and an 18p deletion were subjected to neurological examination., Results: Primary fibroblasts hemizygous for SMCHD1 have a D4Z4 chromatin structure comparable with FSHD2 concomitant with DUX4 expression after transdifferentiation into myocytes. Neurological examination of 18p deletion individuals from two independent families with a moderately sized D4Z4 repeat identified muscle features compatible with FSHD., Conclusions: 18p deletions leading to haploinsufficiency of SMCHD1 , together with a moderately sized FSHD permissive D4Z4 allele, can associate with symptoms and molecular features of FSHD. We propose that patients with 18p deletion should be characterised for their D4Z4 repeat size and haplotype and monitored for clinical features of FSHD., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To examine the relationship of clinical and genetic features of patients with facioscapulohumeral muscular dystrophy (FSHD) with 7-10 residual D4Z4 repeats in a large genetically defined FSHD1 cohort., Methods: We performed a prospective cross-sectional observational study of 74 clinically affected patients with FSHD1. Measures of clinical severity were compared between patients with 1-6 D4Z4 repeats and 7-10 repeats, and included D4Z4 CpG methylation, age at diagnosis, age-adjusted clinical severity score, a muscle pathology grade of quadriceps biopsies (0 = normal, 12 = severe dystrophic changes), quantitative myometry of biopsied muscles, global manual muscle testing scores, and frequency of wheelchair use., Results: Twenty-eight (37.8%) participants had 7-10 D4Z4 repeats, and compared to participants with 1-6 repeats, were diagnosed 6.6 years older (p = 0.17); had lower CpG methylation than would be predicted by D4Z4 repeat size (p = 0.04); had age-adjusted clinical severity 39.8 points lower (p = 0.004); had muscle pathology grades that were 2.4 points less severe (p < 0.0001); had quantitative myometry 28.3% predicted of normal higher (p = 0.002); had global manual muscle testing scores 0.6 higher (p = 0.005); and did not require wheelchairs., Conclusion: Patients with FSHD with 7-10 D4Z4 repeats have milder disease than other genetically defined patients with FSHD1. The lower than predicted methylation in the 7-10 residual repeat group may suggest that additional epigenetic factors play a role in the severity of disease expression., (© 2015 American Academy of Neurology.)

Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD., (© 2015 WILEY PERIODICALS, INC.)

Introduction: Few studies have evaluated the frequency or predisposing factors for respiratory involvement in facioscapulohumeral muscular dystrophy type 1 (FSHD1) and type 2 (FSHD2)., Methods: We performed a prospective cross-sectional observational study of 61 genetically confirmed FSHD participants (53 FSHD1 and 8 FSHD2). Participants underwent bedside pulmonary function testing in sitting and supine positions, a standard clinical history and physical assessment, and manual muscle testing., Results: Restrictive respiratory involvement was suggested in 9.8% (95% confidence interval 2.4-17.3): 7.5% FSHD1 and 25.0% FSHD2 (P = 0.17). Participants with testing suggestive of restrictive lung involvement (n = 6) were more severely affected (P = 0.005), had weaker hip flexion (P = 0.0007), and were more likely to use a wheelchair (P = 0.01)., Conclusions: Restrictive respiratory involvement should be considered in all moderate to severely affected FSHD patients with proximal lower extremity weakness. The higher frequency of restrictive lung disease in FSHD2 seen here requires confirmation in a larger cohort of FSHD2 patients., (© Published 2014 by Wiley Periodicals, Inc.)

Background: Recent studies have proposed a unified genetic model for Facioscapulohumeral muscular dystrophy (FSHD), identifying potential therapeutic targets for future clinical trials. Serum biomarkers related to disease activity will be important for proof of concept or early phase clinical studies., Objective: To identify potential serum biomarkers in FSHD for possible use in future clinical trials., Methods: We performed a prospective cross-sectional study of serum biomarkers in 22 FSHD patients (19 FSHD1, 3 FSHD2) compared to 23 age and gender-matched healthy controls using a commercial multiplex, microsphere-based immune-fluorescent assay of 243 markers (Myriad, Human Discovery MAP 250, v2.0)., Results: 169 markers had values sufficient for analysis. Correction for multiple testing identified 7 biomarkers below a 5% false discovery rate: creatine kinase MB fraction (CKMB, 6.52 fold change, P<0.0001), tissue-type plasminogen activator (PLAT, 1.64 fold change, P<0.0001), myoglobin (2.23 fold change, P=0.0001), epidermal growth factor (EGF, 2.33 fold change, P=0.0004), chemokine (C-C motif) ligand 2 (1.48 fold change, P=0.0004), CD 40 ligand (1.89 fold change, P=0.001), and vitronectin (VTN, 1.28 fold change, P=0.001). Moderate correlations to measures of FSHD disease were seen for CKMB, PLAT, and EGF. Markers in the plasminogen pathway (PLAT, serpin peptidase inhibitor, and VTN) were correlated with each other in FSHD but not healthy controls., Conclusions: Commercial multiplex immune-fluorescent screening is a potentially powerful tool for identifying biomarkers for future FSHD therapeutic trials. Biomarkers identified in this study warrant further study in a larger prospective validation study.

Objective: To investigate the frequency of Coats syndrome and its association with D4Z4 contraction size in patients with facioscapulohumeral muscular dystrophy type 1 (FSHD1)., Methods: We searched a North American FSHD registry and the University of Rochester (UR) FSHD research database, reviewed the literature, and sent surveys to 14 FSHD referral centers in the United States and overseas to identify patients with genetically confirmed FSHD1 with a diagnosis of Coats syndrome., Results: Out of 357 genetically confirmed patients in a North American FSHD registry and 51 patients in the UR database, 3 patients had a self-reported history of Coats disease (0.8%; 95% confidence interval 0.2%-2.2%). In total, we identified 14 patients with FSHD with known genetic contraction size and Coats syndrome confirmed by ophthalmologic examination: 10 from our survey and 4 from the literature. The median age at diagnosis of Coats syndrome was 10 years (interquartile range 14 years). The median D4Z4 fragment size was 13 kilobases (kb) (interquartile range 1 kb). One patient was mosaic (55% 11 kb, and 45% 78 kb)., Conclusions: Coats syndrome is a rare extramuscular complication of FSHD1 associated with large D4Z4 contractions. Closer surveillance for retinal complications is warranted in patients with D4Z4 fragments ≤15 kb.

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 containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.