Key result
Three novel homozygous likely pathogenic HACD1 variants were identified in patients with neonatal-onset generalized muscle weakness, confirming HACD1 as a cause of congenital myopathy.
Why the study?
To date, only two homozygous loss-of-function variants in the HACD1 gene had been reported to cause congenital myopathy.
Case Report (n=3)
Confirms biallelic loss-of-function HACD1 variants as a cause of congenital myopathy, expanding the genotypic spectrum of the disease.
Supports HACD1 testing in select congenital myopathy cases; leaves open validation in larger cohorts before practice change.
Congenital myopathies include a wide range of genetically determined disorders characterized by muscle weakness that usually manifest shortly after birth. To date, two different homozygous loss-of-function variants in the HACD1 gene have been reported to cause congenital myopathy. We identified three patients manifesting with neonatal-onset generalized muscle weakness and motor delay that carried three novel homozygous likely pathogenic HACD1 variants. The two of these changes (c.373_375+2delGAGGT and c.785-1G>T) were predicted to introduce splice site alterations, while one is a nonsense change (c.458G>A). The clinical presentation of our and the previously reported patients was comparable, including the temporally progressive improvement that seems to be characteristic of HACD1-related myopathy. Our findings conclusively confirm the implication of HACD1 in the pathogenesis of congenital myopathies, corroborate the main phenotypic features, and further define the genotypic spectrum of this genetic form of myopathy. Importantly, the genetic diagnosis of HACD1-related myopathy bears impactful prognostic value.
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Abbasi‐Moheb et al. (2020) conducted a case report in Congenital myopathy (n=3). Homozygous loss-of-function HACD1 variants was evaluated on Clinical presentation and genetic diagnosis. Three novel homozygous likely pathogenic HACD1 variants were identified in patients with neonatal-onset generalized muscle weakness, confirming HACD1 as a cause of congenital myopathy.
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