FXR1 – Congenital Myopathy

FXR1 is robustly implicated in autosomal recessive congenital myopathy characterized by multicore lesions, hypotonia, proximal muscle weakness and respiratory insufficiency. Biallelic pathogenic variants clustered in exon 15 of FXR1 define a spectrum ranging from severe neonatal hypotonia with long bone fractures and respiratory failure to milder proximal myopathy with adult survival (PMID:35393337). The phenotype is distinguishable by normal serum creatine kinase, diffuse muscle atrophy sparing quadriceps femoris on imaging, and multicore features on biopsy.

Genetic evidence derives from eight affected individuals across four unrelated families, all harboring rare exon 15 duplications in homozygous or compound heterozygous state (PMID:35393337). Segregation analysis confirmed co-segregation of the variants with disease in sibships. A representative variant is c.1603+725dup, affecting the intronic region adjacent to exon 15. The restriction of pathogenic alleles to this muscle-specific exon underscores a critical role for exon 15 in FXR1P function.

Segregation is supported by at least four additional affected relatives with consistent genotype–phenotype correlation. No pathogenic variants have been reported in control populations at appreciable frequency, and all alleles are absent from gnomAD, satisfying criteria for ultra-rare autosomal recessive inheritance.

Functional studies in a knock-in mouse model carrying exon 15–specific FXR1 mutations recapitulate the human myopathic phenotype, including multicore pathology and muscle weakness, while full FXR1 knockout is neonatal lethal (PMID:30770808). These data demonstrate that hypomorphic exon 15–restricted alleles produce a viable but myopathic phenotype concordant with human disease.

Mechanistically, exon 15 encodes a muscle-specific domain required for FXR1P isoform incorporation into biomolecular condensates in myotubes, and its disruption leads to abnormal RNA granule formation and core degeneration. Rescue of muscle morphology by reintroduction of exon 15–containing transcripts in vitro supports a loss-of-function mechanism specific to muscle isoforms.

Collectively, the clinical, genetic and experimental concordance meets criteria for a Strong ClinGen gene–disease association. FXR1 testing should be considered in autosomal recessive congenital myopathy with multicore lesions.

References

• Journal of medical genetics • 2022 • FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum. PMID:35393337
• Nature communications • 2019 • Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy. PMID:30770808

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