ClinGen Dosage Sensitivity Curation Page

TRPS1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000008.10) (NC_000008.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
31662300 In 2019, Zepeda-Mendoza et al. used chromosomal microarray (CMA), mate-pair sequencing (MPseq), RNA sequencing (RNA-seq), and next generation sequencing (NGS) on an 11-year-old with trichorhinophalangeal syndrome type I. Analysis identified a de novo, intragenic duplication variant in TRPS1 in the proband predicted to cause protein truncation.
21740822 In 2011, Shao et al. described a 17-year-old with trichorhinophalangeal syndrome type 1. Using PCR, the authors identified a de novo, single base insertion in exon 4 of TRPS1. Per the authors, "Occuring prior to the nuclear localization signals (NLS), this mutation (1096insA) is predicted to result in a truncated, nonfunctional TRPS1 protein absent of NLS." Of note, the proband also had severe osteoporosis. Another case of trichorhinophalangeal syndrome type I and severe osteoporosis is described in PMID: 24357341.
11112658 In 2000, L?decke et al. studied 51 unrelated individuals with trichorhinophalangeal syndrome type I and III. The authors employed PCR and direct sequencing to identify potential variants in TRPS1. Analysis identified 35 different variants in TRPS1 in 44 patients with normal chromosomes. There were 24 confirmed sporadic cases and 19 familial cases. Of these variants, 29 were nonsense variants, 1 was a splice site variant, and 5 were missense variants. Only 4 of the sporadic cases involved missense variants.

Haploinsufficiency phenotype comments:

Additional evidence includes: PMID: 23510776 In 2013, Nan et al. used PCR and direct sequencing on an individual with trichorhinophalangeal syndrome type I to identify potential variants in TRPS1. Analysis identified a frameshift variant in TRPS1. Per the authors, ?this deletion is an unquestionable loss-of-function mutation, deleting all functionally important parts of the protein.? This variant was not found in the proband?s unaffected sister. PMID: 28256045 In 2016, Gilman et al. used SNP microarray followed by sequencing of TRPS1 on an individual with autism spectrum disorder (ASD) and Legg-Perthes disease. Analysis identified a frameshift variant (p.Ser1067ArgfsStop3) in TRPS1 resulting in protein truncation. The parents of the proband were unaffected but did not undergo testing. PMID: 23621477 In 2013, Farooq et al. used PCR and sequence analysis on a 9-year-old with trichorhinophalangeal syndrome type I to search for causative variants in TRPS1. The authors identified a nonsense variant (p.R257X) in TRPS1 which they predict results in nonsense-mediated mRNA decay. This variant was absent in the proband's unaffected parents, and is thus de novo. PMID: 30914275 In 2019, Karaca et al. used PCR and Sanger sequencing on an individual with brachydactyly to identify potential variants in TRPS1. The authors noted that pathogenic variants in the genes PTHLH and PDE4D were excluded. Analysis identified a nonsense variant in exon 4 (p. Arg624*). This variant was also present in the proband?s affected mother and sister.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity