MYH3 – Spondylocarpotarsal Synostosis Syndrome

Spondylocarpotarsal synostosis syndrome (SCT; MONDO:0010094) is a rare skeletal dysplasia characterized by vertebral fusion, scoliosis, short stature, and carpal/tarsal synostosis. While most cases are autosomal recessive due to FLNB mutations, multiple studies have identified both heterozygous and biallelic MYH3 (HGNC:7573) variants in SCT patients. MYH3 encodes embryonic myosin heavy chain 3, a key driver of skeletal development.

In autosomal dominant SCT, two independent families harbored protein-altering MYH3 missense variants in exome sequencing (2 probands; c.998C>G (p.Thr333Arg) and c.4031T>C (p.Leu1344Pro)) (PMID:27381093). A separate case report described a de novo heterozygous truncating MYH3 variant in a child with classic SCT and basilar invagination (1 proband; PMID:30228365). Collectively, these three unrelated probands support a dominant mechanism.

Recessive SCT due to MYH3 was uncovered in a cohort of 16 FLNB-negative individuals from multiple families, all carrying compound heterozygous truncating or splice-site variants (e.g., c.4371G>A (p.Trp1457Ter); PMID:29805041). Nine individuals inherited a truncating allele from one parent and six carried the hypomorphic 5' UTR splice variant rs557849165 in trans, indicating a loss-of-function mechanism in the recessive context.

Segregation analysis across five families (2 dominant, 3 recessive) demonstrated co-segregation of MYH3 variants with SCT phenotypes, with unaffected parents transmitting alleles in recessive cases and de novo or vertical transmission in dominant pedigrees. There was no evidence of incomplete penetrance.

The variant spectrum comprises two missense changes affecting the motor domain, multiple truncating and splice variants causing reduced transcript or protein levels, and a recurrent hypomorphic 5' UTR splice variant. No founder alleles have been reported to date in SCT cohorts.

Functional studies in a zebrafish smyhc1R673H model (orthologous to human R672H) recapitulated notochord kinks, scoliosis, vertebral fusions, and muscle defects, all normalized by treatment with the myosin ATPase inhibitor para-aminoblebbistatin (PMID:33016623). In vitro splicing assays confirmed aberrant transcripts from the hypomorphic UTR variant (PMID:29805041).

Together, genetic and experimental data support a dual mechanism whereby dominant missense MYH3 variants exert a dominant-negative effect on myosin motor function, while biallelic truncating/hypomorphic variants act by loss of function. MYH3 testing should be included in diagnostic panels for SCT, particularly in FLNB-negative patients.

Key Take-home: MYH3 is definitively implicated in both autosomal dominant and recessive forms of spondylocarpotarsal synostosis syndrome, warranting inclusion in genetic diagnostic and counseling strategies.

References

• European journal of human genetics : EJHG • 2016 • Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome. PMID:27381093
• Journal of human genetics • 2018 • A novel truncating mutation in MYH3 causes spondylocarpotarsal synostosis syndrome with basilar invagination. PMID:30228365
• American journal of human genetics • 2018 • Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3. PMID:29805041
• EMBO Molecular Medicine • 2020 • MYH3-associated distal arthrogryposis zebrafish model is normalized with para-aminoblebbistatin. PMID:33016623

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