Balanced chromosomal rearrangements new research long non-coding RNAs

Current research now demonstrates a new mechanism for the origin of clinical defects in patients with mostly de novo balanced chromosomal rearrangements (translocations, insertions or inversions). These are the so-called long non-coding RNAs, and because they do not code any proteins their biological role was not clear (sometimes it was considered as a biological trash). But a new research study has shown that lncRNAs may be an important explanation of the origin of several defects.

As a rule, balanced chromosomal rearrangements (BCR) do not cause any clinical problems in the carriers (above possible reproductive consequences). However, many persons with BCR especially with sporadic (de novo) BCR have phenotypic abnormalities. In some cases these defects are caused by physical disruptions in one or two genes affected upon formation of BCR. However some patients with BCR reveal phenotypic defects even without physical damage to any protein-coding genes. The authors examine the role of non-protein-coding RNA in the origin of clinical abnormalities in persons with BCR. The Developmental Genome Anatomy Project recruits persons with BCR and clinical abnormalities. After exclusion of patients with physical disruption of at least one protein-coding gene they found 30 patients where no genes aside from long non-coding RNA (lncRNA) were involved. The authors showed that disruptions of lncRNA were the only possible explanation for clinical manifestations in the patients. So, disruption of the lncRNA TBX2-AS1 from chromosome 17 was found as an explanation of hearing impairment in the girl with t(14;17)(q24.3;q23). Disruption of lnc MEF2C-AS1 was found in two developmentally disabled persons with t(5;7)(q13.3;q21.3) and inv(5)(p12q13.1). lncRNA ENSG00000257522 was disrupted in persons with microcephaly and defects of the corpus callosum and t(3;14)(p22;q13) and t(8;14)(q21.2;q12). There are several more similar examples in the authors’ study. It was shown that disrupted lncRNA may be both very close to the coding gene and be relatively far from such a gene in the linear position but close enough upon formation of the 3-dimentional structure of the gene. The authors discuss the different mechanisms of possible role of lncRNA in rare genetic disorders and recommend analyzing these lncRNA in patients who have no other explanation of their defects.

Andersen R.E. et al. “Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders”. “Human Genetics”, 2024, online ahead of print [published on July 26, 2024].

Chromosome Disorder Outreach Inc. medical geneticist and medical advisor Dr. Iosif Lurie M.D. Ph.D examines newly published research studies to locate the most important and relevant for our members. Synopses of these articles are then posted to our website’s research pages. For more information on any article please contact info@chromodisorder.org