New case of trichorinophalangeal syndrome-like phenotype with a de novo t(2;8)(p16.1;q23.3) translocation which does not disrupt the TRPS1 gene

BMC Medical Genetics

Palma Finelli¹  Angela Ida Pincelli⁶  Lidia Larizza⁴  Guido Grassi³  Chiara Picinelli⁵  Silvia Tabano²  Chiara Castronovo⁵  Mario Perotti⁶  Ilaria Bestetti¹  Milena Crippa⁵ 

[1] Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, via Viotti 3/5, Milan, Italy;Department of Pathophysiology Medical-Surgical and Transplant, Università degli Studi di Milano, Milan, via Sforza 35, Italy;IRCCS MultiMedica, Sesto San Giovanni, Milan, Via Milanese 300, Italy;Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, via Rudini 8, Italy;Medical Cytogenetics and Molecular Genetics Lab, Istituto Auxologico Italiano, Milan, via Ariosto 13, Italy;Medical Clinic, Hospital San Gerardo, Università di Milano-Bicocca, Monza, via Pergolesi 33, Italy

关键词: TRPS1;    TRPS;    Conserved enhancer element;    Reciprocal translocation;   

Others  :  1091881
DOI  :  10.1186/1471-2350-15-52

 received in 2013-08-24, accepted in 2014-04-24,  发布年份 2014

【 摘 要 】

Background

Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterised by distinctive craniofacial and skeletal abnormalities. TRPS is generally associated with mutations in the TRPS1 gene at 8q23.3 or microdeletions of the 8q23.3-q24.11 region. However, three deletions affecting the same chromosome region and a familial translocation t(8;13) co-segregating with TRPS, which do not encompass or disrupt the TRPS1 gene, have been reported. A deregulated expression of TRPS1 has been hypothesised as cause of the TRPS phenotype of these patients.

Case presentation

We report the clinical and molecular characterisation of a 57-year-old Caucasian woman carrying the t(2;8)(p16.1;q23.3) de novo balanced translocation. The proband presented with peculiar clinical features (severe craniofacial dysmorphism, alopecia universalis, severe scoliosis, mitral valve prolapse, mild mental impairment and normal growth parameters) that partially overlap with TRPS I. Mutational and array CGH analyses ruled out any genetic defect affecting TRPS1 or genomic alteration at the translocation breakpoint or elsewhere in the genome. Breakpoint mapping excluded disruption of TRPS1, and revealed that the chromosome 8q23.3 breakpoint was located within the IVS10 of the long intergenic non-coding RNA LINC00536, at approximately 300 kb from the TRPS1 5’ end. Conversely, the 2p16.1 breakpoint mapped within a LINE sequence, in a region that lacks transcriptional regulatory elements. As a result of the translocation, nucleotide base pair additions and deletions were detected at both breakpoint junction fragments, and an evolutionarily conserved VISTA enhancer element from 2p16.1 was relocated at approximately 325 kb from the TRPS1 promoter.

Conclusions

We suggest that the disruption of the genomic architecture of cis regulatory elements downstream the TRPS1 5′ region, combined with the translocation of a novel enhancer element nearby TRPS1, might be the pathogenetic mechanism underpinning the proband’s phenotype. The clinical and genetic characterisation of the present subject allowed us to make a genetic diagnosis in the context of a known syndrome, contributing to a better comprehension of the complex transcriptional regulation of TRPS1 and TRPS ethiopathogenesis.

【 授权许可】

   
2014 Crippa et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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