Homozygous pathogenic MYH3 variant associated with arthrogryposis and lingual dystonia

Introduction : Myosin heavy chain 3 (MYH3) encodes the heavy chain of embryonic myosin 1. Heterozygous pathogenic variants in the MYH3 gene are responsible for distal arthrogryposis 2 and contractures, pterygia and spondylocarpotarsal fusion syndrome 3.
Case report : We report a consanguineous family of four children with a MYH3 homozygous variant associated with complex movement disorders, especially prominent congenital lingual dystonia. Two of them also present multifocal dystonia and the third sibling has cervical dystonia and parkinsonism. They all present typical arthrogryposis and jaw contractures. Parents are asymptomatic.
All four children were homozygous for a missense variant in the MYH3 gene (c.3445G>A, p.Glu1149Lys) detected by whole exome sequencing in a region of loss of heterozygosity. This variant has an extremely low frequency in control populations and was predicted damaging by computational software. Co-segregation and phenotype criteria were applied since the association between the MYH3 gene and arthrogryposis is validated. This variant was therefore classified as likely pathogenic. Another homozygous variant was found in MYH3 gene, although due to insufficient evidence it was considered of uncertain significance. No other significant copy number or single nucleotide variation were found using long-read whole genome sequencing.
Discussion : Besides muscles and bones, MYH3 is also expressed postnatally in the brain including basal ganglia 3, a region frequently dysregulated in dystonia 4. Moreover, it has been proposed that pathogenic variants in MYH3 inhibit TGF-beta signaling 5. The involvement of this pathway has already been reported in generalized dystonia 6. We postulate that MYH3 variants are responsible for dystonia through inhibition of the TGF-beta pathway. In vitro analysis are ongoing to assess TGF-beta signaling inhibition in transfected plasmids 7.
Conclusion : We have extended the phenotype of MYH3-associated arthrogryposis to include movement disorders, which may have been under-diagnosed to date.