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.
- muscle misease
- 18p deletion
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SS and SMvdM are senior authors.
Contributors JB and SMvdM conceived the study. JB designed the experiments and analysed the data. JB, RG, KRS, RJLFL, PJvdV, CALR and AvdH performed the experiments. CC, NC, LF, VM, JC, MK, CMD-S, PH, JDC, RT, SS and SJT contributed to clinical data and patient material. JB, SMvdM, SS and CMD-S wrote the manuscript.
Funding This study was supported by grants from the US National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS) P01NS069539, and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01AR045203 and R01AR066248, the Prinses Beatrix Spierfonds (W.OP14-01 and W.OR14-04), and Spieren voor Spieren.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Institutional Review Board of the University of Rochester Medical Center, Institutional Review Board of Leiden University Medical Center, and Institutional Review Board of the University of Texas Health Science Center at San Antonio.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it was published Online First. A statement about co-senior authorship has been added.