Clinical and Molecular Heterogeneity of MYH3-Related Arthrogryposis with a Novel MYH3 Variant

Arthrogryposis consists of a heterogeneous group of congenital disorders characterized by multiple joint contractures. Distal arthrogryposes (DAs) are often caused by pathogenic variants in fast-twitch muscle protein genes, including MYH3, nosologically linked to DA2A and DA2B.

We evaluated two siblings with features suggestive of arthrogryposis through detailed clinical examination, radiographic imaging, audiological assessment, and targeted next-generation sequencing (NGS) for skeletal dysplasias and an arthrogryposis panel, including MYH3. Variants were confirmed by Sanger sequencing, and segregation analysis was performed in available relatives.

Both patients harbored three heterozygous MYH3 variants: two maternally inherited in cis (c.749G>A and c.787G>T) and one paternally inherited in trans (c.4130_4138del), currently classified as variants of uncertain significance (VUS) and likely pathogenic, respectively. The female patient presented with a short neck, hand contractures, cubitus valgus, a widened internipple distance, and severe thoracolumbar scoliosis. The male sibling showed craniofacial dysmorphisms, more extensive musculoskeletal anomalies, and moderate-to-severe sensorineural hearing loss. The segregation analysis suggests an MYH3 autosomal recessive inheritance pattern.

This report broadens the phenotypic spectrum of MYH3-related disorders, suggesting potential involvement in atypical DA phenotypes resembling DA4 (scoliosis) and DA6 (hearing loss), for which causative genes remain unknown. Comprehensive molecular testing and segregation analysis are essential to clarify genotype-phenotype correlations in congenital contracture syndromes.