BMJ neurology open · 2025
Clinical and genetic analysis of a family with myopathy caused by an FHL1 gene variant.
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Zhang Shuyi, Cao Xiaoli, Wu Xianghong, Huang Wen
Аннотация
BACKGROUND: Variants in the FHL1 gene are associated with a spectrum of rare X-linked hereditary myopathies. This study describes the clinical presentation and genetic basis of a novel FHL1 variant identified in a Chinese family with an inherited myopathy, aiming to delineate its phenotypic and genotypic characteristics.
METHODS: Clinical data were collected from two symptomatic family members. The proband underwent a muscle biopsy. Genetic analysis was performed using whole-exome sequencing and Sanger sequencing of peripheral blood DNA. Bioinformatic tools were employed to predict the pathogenicity of the variant and its impact on protein structure and stability. Wild-type and mutant FHL1 constructs were transfected into 293 T cells to compare mRNA and protein expression levels via quantitative PCR and Western blot.
RESULTS: Affected family members exhibited progressive lower limb weakness and muscle atrophy. Muscle biopsy revealed mild myopathic changes without reducing bodies. A heterozygous FHL1 c.505T>C (p.C169R) variant was identified in the proband and other affected family members, while her nephew carried a hemizygous variant. Bioinformatics analysis predicted the variant to be damaging, and structural analysis indicated altered secondary structure and reduced protein stability. While mRNA levels remained unchanged in transfected 293 T cells, mutant FHL1 protein expression was significantly reduced in this heterologous system.
CONCLUSION: The FHL1 c.505T>C (p.C169R) variant is likely pathogenic and associated with a familial myopathy. The reduction in mutant protein expression may contribute to the disease mechanism. This finding expands the spectrum of FHL1-related myopathy reported in the Chinese population and underscores the importance of integrated genetic and clinical analyses for diagnosis.
METHODS: Clinical data were collected from two symptomatic family members. The proband underwent a muscle biopsy. Genetic analysis was performed using whole-exome sequencing and Sanger sequencing of peripheral blood DNA. Bioinformatic tools were employed to predict the pathogenicity of the variant and its impact on protein structure and stability. Wild-type and mutant FHL1 constructs were transfected into 293 T cells to compare mRNA and protein expression levels via quantitative PCR and Western blot.
RESULTS: Affected family members exhibited progressive lower limb weakness and muscle atrophy. Muscle biopsy revealed mild myopathic changes without reducing bodies. A heterozygous FHL1 c.505T>C (p.C169R) variant was identified in the proband and other affected family members, while her nephew carried a hemizygous variant. Bioinformatics analysis predicted the variant to be damaging, and structural analysis indicated altered secondary structure and reduced protein stability. While mRNA levels remained unchanged in transfected 293 T cells, mutant FHL1 protein expression was significantly reduced in this heterologous system.
CONCLUSION: The FHL1 c.505T>C (p.C169R) variant is likely pathogenic and associated with a familial myopathy. The reduction in mutant protein expression may contribute to the disease mechanism. This finding expands the spectrum of FHL1-related myopathy reported in the Chinese population and underscores the importance of integrated genetic and clinical analyses for diagnosis.