Liangliang Qiu 1 , Zhixian Ye 1 , Lin Lin 1 , Lili Wang 1 , Xiaodan Lin 1 , Junjie He 1 , Feng Lin 1 , Guorong Xu 1 , Naiqing Cai 1 , Ming Jin 1 , Haizhu Chen 1 , Minting Lin 1,2 , Ning Wang 3,2 , Zhiqiang Wang 3,2 Show Affiliations »
Abstract
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. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
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 . © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
Entities: Disease
Gene
Species
Keywords:
neuromuscular disease
Mesh： See more »
Year: 2020
PMID： 32170003 DOI： 10.1136/jmedgenet-2019-106638
Source DB: PubMed Journal: J Med Genet ISSN： 0022-2593 Impact factor: 6.318