X-Linked Spondyloepiphyseal Dysplasia Tarda (SEDT) via the TRAPPC2 Gene

X-linked spondyloepiphyseal dysplasia tarda (SEDT; OMIM#313400) is characterized by disproportionately short stature with a short trunk and an arm span significantly greater than height. At birth, affected males are normal in length and have normal body proportions. Around age six to eight years, those affected males begin to exhibit retarded linear growth. Final adult height is typically 4'10" to 5'6". Progressive joint and back pain with osteoarthritis ensues; hip, knee, and shoulder joints are commonly involved but to a variable degree. Hip replacement is often required as early as age 40 years (Tiller & Hannig. GeneReviews. 2011).

X-linked SEDT is inherited in an X-linked recessive manner. TRAPPC2 (previously known as SEDL) is the only gene in which variants are known to cause X-linked SEDT. TRAPPC2 encodes sedlin, an evolutionarily-conserved and ubiquitously-expressed protein whose function remains poorly understood. Based on the function of the yeast homolog, sedlin may be involved with intracellular protein trafficking, as part of the TRAPP (transport protein particle) complex (Jang et al. J Biol Chem. 277:49863–49869, 2002). Other studies have demonstrated localization of sedlin to the nucleus, where it interacts with various transcription factors (Liu et al. J Cell Biochem 109:1129–1133, 2010). Small deletions causing frameshifts and splice site variants in TRAPPC2 were found in more than half of reported X-linked SEDT cases (Savarirayan et al. Eur J Hum Genet 11:639–642, 2003). Missense and nonsense variants were a relatively less common type of variant (Gedeon et al. Am J Hum Genet 68:1386–1397, 2001). Large deletions involving single or multiple exons have also been documented in different studies (Gedeon et al. 2001; Shaw et al. Clin Genet 64:235–242, 2003; Fiedler et al. Hum Mutat 24:103, 2004), though cumulatively accounting for only a small portion of cases.

Sequencing of TRAPPC2 is predicted to detect disease variants in more than 80% of males with a clinical diagnosis of X-linked SEDT (Gedeon et al. 2001; Fiedler et al. 2004). Note: TRAPPC2 gene deletions are suspected in males based on failed amplification of single or multiple exons. Some of these large deletions would not be detected in female carriers by sequence analysis.

This test provides full coverage of all coding exons of the TRAPPC2 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).