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

Martina Servetti; Livia Pisciotta; Elisa Tassano; Maria Cerminara; Lino Nobili; Silvia Boeri; Giulia Rosti; Margherita Lerone; Maria Teresa Divizia; Patrizia Ronchetto; Aldamaria Puliti

doi:10.3389/fgene.2021.732002

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

Front Genet. 2021 Sep 21:12:732002. doi: 10.3389/fgene.2021.732002. eCollection 2021.

Authors

Martina Servetti^{1

2}, Livia Pisciotta^{1

3}, Elisa Tassano⁴, Maria Cerminara¹, Lino Nobili^{1

5}, Silvia Boeri^{1

5}, Giulia Rosti¹, Margherita Lerone², Maria Teresa Divizia², Patrizia Ronchetto⁴, Aldamaria Puliti^{1

2}

Affiliations

¹ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy.
² Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
³ Child Neuropsychiatry Unit, ASST Fatebenefratelli Sacco, Milano, Italy.
⁴ Human Genetics Laboratory, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
⁵ Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Genoa, Italy.

Abstract

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.

Keywords: additive effect; antisense gene; array-CGH; long non-coding genes; microdeletion; microduplication; oligogenic disease; variants of uncertain significance.