MYH3-Related Distal Arthrogryposis via the MYH3 Gene

Distal arthrogryposis (DA) syndromes are a group of multiple congenital contracture disorders with distal joint involvement, variable clinical expression, and autosomal dominant inheritance (Bamshad et al. Am J Med Genet 65:277- 281, 1996). Distal arthrogryposis 2A (DA2A, OMIM 193700), or Freeman-Sheldon syndrome (FSS), is the most severe DA syndrome. Patients with FSS have, in addition to distal joint contractures, facial findings secondary to contractures of facial muscles. A small mouth with a whistling-like appearance is a universal finding. The eyes are often deep-set and the nasal bridge wide. Other findings include epicanthal folds, strabismus, bilateral ptosis, and reduced eyelid size. FSS patients also often have H-shaped dimpling of the chin, small nose, long philtrum, high palate, small tongue, and nasal speech. Skeletal finding include ulnar deviation of the hands, camptodactyly, kyphoscoliosis, clubfoot, and contractures of the knees or hips. Distal arthrogryposis 2B (DA2B, OMIM 601680), or Sheldon-Hall syndrome (SHS) is the most common DA syndrome. Clinically, SHS is less severe than FSS but more severe than TPM2-related DA (DA1). Facial features reminiscent of FSS are present but are less pronounced.

MYH3-associated distal arthrogryposis syndromes are inherited as autosomal dominant disorders. Missense variants affecting catalytic activity of the embryonic skeletal muscle myosin heavy chain protein are a known cause of FSS (Toydemir et al. Nat Genet 38:561-565, 2006; Tajsharghi et al. Arch Neurol 65:1083-1090, 2008). In contrast, variants in MYH3 which alter residues that interact with other proteins of the contractile apparatus, such as actin and troponin, have been shown to cause SHS (Toydemir et al. 2006). Thus far, with one exception, amino acid substitutions are the only form of MYH3 variants identified in patients. A single amino acid deletion represents the one exception, and this change was found in two unrelated SHS patients (Toydemir et al. 2006). SHS is also caused by variants in the TNNT3 and TNNI2 genes (Sung et al. Am J Hum Genet 73:212-4, 2003).

MYH3 variants appear to be a common cause of Freeman-Sheldon syndrome. Variants were found in 26 of 28 cases, 75% of which were sporadic (Toydemir et al. 2006). Among 38 Sheldon-Hall syndrome patients who tested negative for variants in TNNI2 or TNNT3, 12 were found to have MYH3 variants.

This test provides full coverage of all coding exons of the MYH3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).