Purpose To analyse the clinical spectrum, genetic features, specific D4Z4 hypomethylation status and genotype–phenotype correlations for somatic mosaicism in facioscapulohumeral dystrophy (FSHD).
Methods This was a prospective, hospital-based, case–control, observational study of 35 participants with FSHD with somatic mosaicism recruited over 10 years, with 17 penetrant patients and 18 non-penetrant mutation carriers. This study also included a univariate comparison of 17 paired mosaic and non-mosaic patients with FSHD.
Results Mosaic participants with FSHD varied in age of diagnosis (median 45; range 15–65 years), muscle strength (FSHD clinical score median 0; range 0–10 points), clinical severity (age-corrected clinical severity score (ACSS) median 0; range 0–467 points), D4Z4 repeats (median 3; range 2–5 units), mosaic proportion (median 55%; range 27%–72%) and D4Z4 methylation extent (median 49.82%; range 27.17%–64.51%). The genotypic severity scale and D4Z4 methylation extent were significantly associated with ACSS (p1=0.003; p2=0.002). Among the matched pairs, the 17 mosaic patients had shorter D4Z4 repeats, lower FSHD clinical scores and lower ACSS than non-mosaic patients. Additionally, 34 of 35 (97%) participants carried two mosaic arrays, while a single patient had three mosaic arrays (3%). Two cases also carried four-type non-mosaic arrays on chromosome 10 (translocation configuration).
Conclusions Broadly, this large mosaic FSHD cohort exhibited significant clinical heterogeneity and relatively slight disease severity. Both genotypic severity scale and D4Z4 hypomethylation status served as modifiers of clinical phenotypes. Consistent with previous reports, mitotic interchromosomal/intrachromosomal gene conversion without crossover was here identified as a major genetic mechanism underlying mosaic FSHD.
- neuromuscular disease
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Contributors LQ and ZW planned the study and drafted the manuscript. LQ, ZY, LL, LW, XL, JH and ZW provided the clinical diagnosis of mosaic patients with FSHD and performed Southern blotting analysis. FL, GX, NC, MJ, HC and ML contributed to acquisition and analysis. LQ and ZY contributed to data interpretation. NW and ZW were responsible for the overall content and are the corresponding authors. All authors provided administrative, technical and material support.
Funding This work was funded by grants from the National Natural Science Foundation of China (81671237, U1505222, Beijing), the Joint Fund for Program of Science Innovation of Fujian Province, China (2016Y9010) and the National Natural Science Foundation of Fujian Province, China (2017J01196).
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval This study was approved by the Ethics Committee for Medical Research of the First Affiliated Hospital of Fujian Medical University (2016). Written informed consent was obtained from each participant before recruitment into the study.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data can be reused upon reasonable request.