Distal Arthrogryposis 2B (Sheldon-Hall Syndrome) via the TNNI2 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). Clinically, Sheldon-Hall syndrome is intermediate between Freeman-Sheldon syndrome (FSS; DA2A, OMIM 193700) and TPM2-related DA (DA1; OMIM 108120). Initially, individuals with findings shared by both DA1 and Freeman-Sheldon syndrome were classified as variant Freeman-Sheldon syndrome (Krakowiak et al. Am J Hum Genet 60:426-432, 1997) but are now known as Sheldon-Hall syndrome or DA2B (OMIM 601680). Sheldon-Hall syndrome is the most common DA syndrome. Facial features in Sheldon-Hall syndrome are reminiscent of, but less pronounced than, those of Freeman-Sheldon syndrome. Patients have been described with mild micrognathia and narrow palpebral fissures (Kimber et al. Neurology 67:597-601, 2006). The original phenotypic description included triangular face, down-slating palpebral fissures, prominent nasolabial folds, and small mouth (Krakowiak et al. 1997). Notably, Sheldon-Hall syndrome patients lack the whistling-like appearance universal among Freeman-Sheldon syndrome patients. Skeletal findings include severe camptodactyly, ulnar deviation, and club foot or flexible flatfoot (Sung et al. Am J Hum Genet 72:681-690, 2003). Remarkable variation in phenotypic manifestation has been described (Shrimpton and Hoo. Eur J Hum Genet 49:201-206, 2006). Muscle biopsies from patients with TNNI2-related DA2B have been described with variability of fiber size, internally localized nuclei, and increased interstitial connective tissue (Kimber et al. 2006).

Distal arthrogryposis 2B (Sheldon-Hall syndrome) is inherited as an autosomal dominant disorder due to variants in the TNNI2, TNNT3, and MYH3 genes. In the TNNI2 gene, deletions involving one amino acid, nonsense variants, and missense variants in the carboxyl terminus have been reported.

TNNI2 appears to be a less common cause of Sheldon-Hall syndrome than MYH3 variants (Toydemir et al. Nat Genet 38:561-565, 2006). Among fourteen individuals with Freeman-Sheldon syndrome, none were found to have TNNI2 variants (Sung et al. 2003).

This test provides full coverage of all coding exons of the TNNI2 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).