Distal Arthrogryposis Panel

Distal arthrogryposis (DA) syndromes are a group of multiple congenital contracture disorders with distal joint involvement, variable clinical expression, and most often autosomal dominant inheritance (Bamshad et al. 1996). Distal arthrogryposis 2A (DA2A), also called 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 findings include ulnar deviation of the hands, camptodactyly, kyphoscoliosis, clubfoot, and contractures of the knees or hips. Distal arthrogryposis 2B (DA2B), 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. Distal arthrogryposis 1A (DA1A) is characterized clinically by clubfoot, camptodactyly, and hypoplasia or absence of interphalangeal creases. Although the pattern of affected joints is consistent, the degree to which the joints are affected is highly variable (Bamshad et al. 2009). As a result of phenotypic and genotypic overlap, it has been proposed that DA1A and DA2B represent extremes of a single clinical entity (Beck at al. 2013). Distal arthrogryposis type 5D (DA5D) is an autosomal recessive DA syndrome with unique facial features (McMillin et al. 2013). Arthrogryposis DA5D affects the distal joints as well as extension contractures of the knee. Camptodacytly is more severe in the fingers than the toes with the wrist and thumbs being adducted. The feet are affected by talipes equinovarus and/or calcaneovalgus deformity. Facial findings include ptosis, which can be unilateral or more severe on one side, micrognathia, arched eye-brows, a bulbous nose that is upturned, and an over-all rounded face. Unlike other DA5 phenotypes, ophthalmoplegia is not a finding of DA5D (McMillin et al. 2013).

Distal Arthrogryposes (DA) is a major subgroup of heterogeneous disorders of Arthrogryposis multiplex congenital (AMC). At least ten different forms of DA (DA1-10) have been reported, and DA1, DA2B (Sheldon-Hall syndrome) and DA2A (Freeman-Sheldon syndrome) are the most common DAs (Bamshad et al. 2009). Genes associated with DA encode components of the contractile apparatus of skeletal muscle. Variants in MYH3 are the most common known cause of DA (Toydemir et al. 2006). This panel includes 11 genes associated with DA: CHST14, ECEL1, FBN2, MYBPC1, MYH3, MYH8, NALCN, PIEZO2, TNNI2, TNNT3 and TPM2. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, except that ECEL and CHST14 pathogenic variants are inherited in an autosome recessive manner (McMillin et al. 2013; Sonoda et al. 2000). A wide variety of causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported. Large deletions/duplications and complex genomic rearrangements have also been reported in two genes (FBN2 and NALCN) (Human Gene Mutation Database). See individual gene test descriptions for more information on molecular biology of gene products, and spectra of pathogenic variants.

MYH3 pathogenic variants appear to be a common cause of FSS and SHS. Pathogenic variants in MYH3 contribute approximately 90% of the cases of FSS and 40% of SHS cases (Bamshad et al. 2009). Pathogenic MYH3 variants were found in 26 of 28 cases (FSS or SHS), 75% of which were sporadic (Toydemir et al. 2006). TNNI2 appears to be a less common cause of SHS than MYH3 (Toydemir et al. 2006). Among 47 Distal Arthrogryposis families, one was found to have a TNNT3 pathogenic variant (Sung et al. 2003). Variants in CHST14, ECEL1, FBN2, MYBPC1, MYH8, NALCN, PIEZO2 and TPM2 have been reported in individual cases associated with Distal Arthrogryposis, and appear to be infrequent causes of disease.

Among the 11 genes in Distal Arthrogryposis NGS panel, gross deletions or duplications not detectable by Sanger sequencing were only reported in FBN2 and NALCN as individual cases, and no statistical data is yet available (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.5% coverage of all coding exons of the genes 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 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).