Article Text
Abstract
Background Biallelic pathogenic variants in FXR1 have recently been associated with two congenital myopathy phenotypes: a severe form associated with hypotonia, long bone fractures, respiratory insufficiency and infantile death, and a milder form characterised by proximal muscle weakness with survival into adulthood.
Objective We report eight patients from four unrelated families with biallelic pathogenic variants in exon 15 of FXR1.
Methods Whole exome sequencing was used to detect variants in FXR1.
Results Common clinical features were noted for all patients, which included proximal myopathy, normal serum creatine kinase levels and diffuse muscle atrophy with relative preservation of the quadriceps femoris muscle on muscle imaging. Additionally, some patients with FXR1-related myopathy had respiratory involvement and required bilevel positive airway pressure support. Muscle biopsy showed multi-minicores and type I fibre predominance with internalised nuclei.
Conclusion FXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants in FXR1 can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype–phenotype correlations difficult. Our work broadens the phenotypic spectrum of FXR1-related congenital myopathy.
- Neuromuscular Diseases
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Footnotes
VS and GY are joint senior authors.
Twitter @Gianina_Natoli
Contributors MM, CL, MEF, SKG, DA, HT, SD, DS, CB, VS and GY recruited and phenotyped the patients. MA, JD, SS, KN, GR, KC and ZV conducted molecular analyses and bioinformatics analysis of whole exome sequencing data. AH-L and DO conducted neuropathological studies. MM, VS and GY designed the study, and wrote the manuscript. VS and GY provided overall study supervision. All authors critically reviewed the manuscript.
Funding MYO-SEQ was funded by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, Samantha J. Brazzo Foundation, LGMD2D Foundation and Kurt+Peter Foundation, Muscular Dystrophy UK, and Coalition to Cure Calpain 3. Analysis was provided by the Broad Institute of MIT and Harvard Centre for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900, and in part by National Human Genome Research Institute grant R01 HG009141. GR is funded by the NHMRC (APP1122952 and APP2002640). The work in C.G. Bönnemann’s laboratory is supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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