Brain-Enriched Coding and Long Non-coding RNA Genes Are Overrepresented in Recurrent Neurodevelopmental Disorder CNVs

Alinejad‐Rokny, Hamid; Heng, Julian Ik‐Tsen; Forrest, Alistair R.R.

doi:10.1016/j.celrep.2020.108307

Cited by 24 publications

(33 citation statements)

References 64 publications

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“…In the Decipher databases no patients have been reported with CNVs overlapping with the duplication, while several patients have been reported with the same deletion, many of whom present ID, one presenting with intrauterine growth retardation (IUGR) and hyperechogenic kidneys, and one presenting with diabetes. In our series of patients, ten had proximal breakpoints downstream to those presented in [44], although the brain-enriched coding and lncRNA genes are the same (respectively, four and five, Table 2, [44]). IUGR was present in one patient with deletion and in another with duplication.…”

Section: Discussionmentioning

confidence: 71%

“…A confirmation of 17q12 recurrent CNVs' strong association with neurodevelopmental disorders has been recently highlighted considering brain-enriched coding and long noncoding (lnc) RNA genes [44]. In particular, authors reported two patients: the former carried a duplication sizing 40 Mb not involving brain-enriched genes but encompassing five lncRNAs; the latter carried a deletion sizing 1.410 Mb involving four brain-enriched genes and five lncRNAs.…”

Section: Discussionmentioning

confidence: 96%

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17q12 Recurrent Deletions and Duplications: Description of a Case Series with Neuropsychiatric Phenotype

Milone

Tancredi

Cosenza

et al. 2021

Genes

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Syndromic neurodevelopmental disorders are usually investigated through genetics technologies, within which array comparative genomic hybridization (Array-CGH) is still considered the first-tier clinical diagnostic test. Among recurrent syndromic imbalances, 17q12 deletions and duplications are characterized by neurodevelopmental disorders associated with visceral developmental disorders, although expressive variability is common. Here we describe a case series of 12 patients with 17q12 chromosomal imbalances, in order to expand the phenotypic characterization of these recurrent syndromes whose diagnosis is often underestimated, especially if only mild traits are present. Gene content and genotype-phenotype correlations have been discussed, with special regard to neuropsychiatric features, whose impact often requires etiologic analysis.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 96%

17q12 Recurrent Deletions and Duplications: Description of a Case Series with Neuropsychiatric Phenotype

Milone

Tancredi

Cosenza

et al. 2021

Genes

View full text Add to dashboard Cite

show abstract

“…In fact, although the molecular function of PTCHD1-AS is still to be clearly elucidated, it has been demonstrated that its disruption diminished miniature excitatory postsynaptic current frequency in iPSC-derived neurons from subjects with ASD, thus supporting a role for this long noncoding RNA in the etiology of ASD (Ross et al, 2020). Interest on regulatory elements of gene expressions, like lncRNA and regulatory enhancer elements, and their involvement in brain disorders has been recently increased and new tools have been applicated for their detection, as those implicated in ASD and Schizofrenia (Piluso et al, 2019;Alinejad-Rokny et al, 2020). Deletions and duplications may overlap TDBs between two flanking topological associated domains causing a dysregulation of chromatin organization and, in turn, a dysregulation of implicated genes which ultimately affects the patient's phenotype.…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs

et al. 2021

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Neurodevelopmental disorders (NDDs) are a heterogeneous class of brain diseases, with a complex genetic basis estimated to account for up to 50% of cases. Nevertheless, genetic diagnostic yield is about 20%. Array-comparative genomic hybridization (array-CGH) is an established first-level diagnostic test able to detect pathogenic copy number variants (CNVs), however, most identified variants remain of uncertain significance (VUS). Failure of interpretation of VUSs may depend on various factors, including complexity of clinical phenotypes and inconsistency of genotype-phenotype correlations. Indeed, although most NDD-associated CNVs are de novo, transmission from unaffected parents to affected children of CNVs with high risk for NDDs has been observed. Moreover, variability of genetic components overlapped by CNVs, such as long non-coding genes, genomic regions with long-range effects, and additive effects of multiple CNVs can make CNV interpretation challenging. We report on 12 patients with complex phenotypes possibly explained by complex genetic mechanisms, including involvement of antisense genes and boundaries of topologically associating domains. Eight among the 12 patients carried two CNVs, either de novo or inherited, respectively, by each of their healthy parents, that could additively contribute to the patients’ phenotype. CNVs overlapped either known NDD-associated or novel candidate genes (PTPRD, BUD13, GLRA3, MIR4465, ABHD4, and WSCD2). Bioinformatic enrichment analyses showed that genes overlapped by the co-occurring CNVs have synergistic roles in biological processes fundamental in neurodevelopment. Double CNVs could concur in producing deleterious effects, according to a two-hit model, thus explaining the patients’ phenotypes and the incomplete penetrance, and variable expressivity, associated with the single variants. Overall, our findings could contribute to the knowledge on clinical and genetic diagnosis of complex forms of NDD.

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“…Here, we focus on ID and classify ID-relevant lncRNAs based on their known, or proposed, functions ( Figure 1 ; Table 1 ) [ 55 , 68 , 107 , 108 , 109 ].…”

Section: Lncrnas In Id and Related Nddmentioning

confidence: 99%

The Emerging Roles of Long Non-Coding RNAs in Intellectual Disability and Related Neurodevelopmental Disorders

Liaci

Prandi

Pavinato

et al. 2022

IJMS

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In the human brain, long non-coding RNAs (lncRNAs) are widely expressed in an exquisitely temporally and spatially regulated manner, thus suggesting their contribution to normal brain development and their probable involvement in the molecular pathology of neurodevelopmental disorders (NDD). Bypassing the classic protein-centric conception of disease mechanisms, some studies have been conducted to identify and characterize the putative roles of non-coding sequences in the genetic pathogenesis and diagnosis of complex diseases. However, their involvement in NDD, and more specifically in intellectual disability (ID), is still poorly documented and only a few genomic alterations affecting the lncRNAs function and/or expression have been causally linked to the disease endophenotype. Considering that a significant fraction of patients still lacks a genetic or molecular explanation, we expect that a deeper investigation of the non-coding genome will unravel novel pathogenic mechanisms, opening new translational opportunities. Here, we present evidence of the possible involvement of many lncRNAs in the etiology of different forms of ID and NDD, grouping the candidate disease-genes in the most frequently affected cellular processes in which ID-risk genes were previously collected. We also illustrate new approaches for the identification and prioritization of NDD-risk lncRNAs, together with the current strategies to exploit them in diagnosis.

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Brain-Enriched Coding and Long Non-coding RNA Genes Are Overrepresented in Recurrent Neurodevelopmental Disorder CNVs

Cited by 24 publications

References 64 publications

17q12 Recurrent Deletions and Duplications: Description of a Case Series with Neuropsychiatric Phenotype

17q12 Recurrent Deletions and Duplications: Description of a Case Series with Neuropsychiatric Phenotype

Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs

The Emerging Roles of Long Non-Coding RNAs in Intellectual Disability and Related Neurodevelopmental Disorders

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