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

Abstract

BackgroundTrichorhinophalangeal 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 presentationWe 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.ConclusionsWe 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.

Comprehensive analysis of the aberrantly expressed lncRNA‑associated ceRNA network in breast cancer

“…Li et al (37) identified that the lncRNA ADAMTS9-AS1 served as a novel prognostic biomarker for clinical application in esophageal squamous cell carcinoma. Crippa et al (38) hypothesized that LINC00536 disruption may have contributed to the onset of the clinical trichorhinophalangeal syndrome-like phenotype. Wang et al (39) suggested that WT1 was overexpressed in human hepatocellular carcinoma tissues, and was negatively correlated with overall survival in patients with hepatocellular carcinoma.…”

Artificial Intelligence in Epigenetic Studies: Shedding Light on Rare Diseases

“…Rs116446171 is located near IRF4, DUSP22, and EXOC2, which are implicated in a variety of lymphoid cancers and might represent an important non-coding variant for WM risk (McMaster et al, 2018). Crippa et al (2014) used a probabilistic HMM applied to human embryonic stem cell (HMES) to identify putative regulatory sequences in ChIP-seq data of a patient with trichorhinophalangeal syndrome (TRPS, ORPHA:324764), a complex autosomal dominant malformative disorder, characterized by distinctive craniofacial and skeletal abnormalities.…”

“… Crippa et al (2014) used a probabilistic HMM applied to human embryonic stem cell (HMES) to identify putative regulatory sequences in ChIP-seq data of a patient with trichorhinophalangeal syndrome (TRPS, ORPHA:324764), a complex autosomal dominant malformative disorder, characterized by distinctive craniofacial and skeletal abnormalities.…”

Trichorhinopharyngeal Syndrome Type 1 and Trisomy 21: A Patient with 2 Genetic Mutations

“…It was first described in 1966 by Giedion based on three main features of sparse hair, bulbous nasal tip, and short deformed fingers. 1 TRPS Type I is generally associated with mutations or microdeletions in the TRPS1 gene on chromosome 8q23.3, with translocations on this chromosomal arm also reported. 1 The prevalence of TRPS Type I is unknown due to varying and subtle presenting features.…”