Tricho-Rhino-Phalangeal Syndrome Types I and III via the TRPS1 Gene

Tricho-rhino-phalangeal syndrome (TRPS) is a malformation syndrome characterized by craniofacial and skeletal abnormalities. Three types of TRPS have been described. TRPS type I (OMIM#190350) is characterized by sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature (Momeni et al. Nature Genet 24:71-74, 2000). TRPS type II (aka Langer-Giedion syndrome, OMIM#150230) shares common clinical manifestations with TRPS I. TRPS type III (OMIM#190351) shows the same dysmorphic features as TRPS I but more severe shortening of all phalanges and metacarpals, and severe short stature (<-2SD). TRPS III has been considered the most severe form of the TRPS spectrum (Ludecke et al. Am J Hum Genet 68:81-91, 2001).

Tricho-rhino-phalangeal syndrome (TRPS) is inherited in an autosomal dominant manner. Type I and type III TRPS are caused by variants in the TRPS1 gene, while TRPS type II is a contiguous gene deletion syndrome involving EXT1 gene. TRPS1 encodes a zinc finger transcription factor, which has 2 potential nuclear localization signals (Kaiser et al. Eur J Hum Genet 12:121-126, 2004) and an unusual combination of different zinc-finger motifs including C2H2-type, IKAROS-type, and GATA-type motifs (Momeni et al. Nat Genet 24:71-74, 2000). Most disease-causing variants in TRPS1 are missense, nonsense and frameshift variants. It has been demonstrated that most patients with nonsense variants show the TRPS I phenotype, while patients with missense variants in the GATA-type zinc-finger show the TRPS III phenotype (Momeni et al. 2000; Ludecke et al. Am J Hum Genet 68:81-91, 2001; Hatamura et al. Clin Genet 59:366–367, 2001; Hilton et al. J Hum Genet 47:103-106, 2002; Piccione et al. Am J Med Genet 149A:1837-1841, 2009).

This test is predicted to detect disease variants in up to 80% of TRPS I/III cases (Momeni et al. 2000; Ludecke et al. 2001).

This test provides full coverage of all coding exons of the TRPS1 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).