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Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III

Lookup NU author(s): Professor Tim Goodship


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Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydaayly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Publication metadata

Author(s): Goodship THJ; Ludecke HJ; Schaper J; Meinecke P; Momeni P; Gross S; von Holtum D; Hirche H; Abramowicz MJ; Albrecht B; Apacik C; Christen HJ; Claussen U; Devriendt K; Fastnacht E; Forderer A; Friedrich U; Greiwe M; Hamm H; Hennekam RCM; Hinkel GK; Hoeltzenbein M; Kayserili H; Majewski F; Mathieu M; McLeod R; Midro AT; Moog U; Nagai T; Niikawa N; Orstavik KH; Plochl E; Seitz C; Schmidtke J; Tranebjaerg L; Tsukahara M; Wittwer B; Zabel B; Gillessen-Kaesbach G; Horsthemke B

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2001

Volume: 68

Issue: 1

Pages: 81-91

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1086/316926


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