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

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

doi:10.3389/fgene.2021.732002

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.

Highlights

Neurodevelopmental disorders (NDDs) are a heterogeneous class of conditions involving the brain, including intellectual disability and autism spectrum disorder (ASD), that affect about 1–3% of children (Miller et al, 2010)
To evaluate the pathogenicity of variants we focused on the following criteria: 1) patients with multiple copy number variants (CNVs), enclosing NDD genes, which could have additive effects on the patients’ phenotype on the basis of results from gene enrichment and protein-protein interactions analyses; 2) patients with CNVs encompassing regions that control the expression of known NDD genes, including those with potential long-range effects; 3) patients whose CNVs encompass genes not yet reported as NDD-associated, but whose expression profile and function suggest a possible involvement in the disease, when at least another patient is reported with a similar CNV and phenotype in publically available databases
The main clinical features were represented by a variable degree of intellectual disability, in three cases associated with a diagnosed ASD, and epilepsy

Summary

Introduction

Neurodevelopmental disorders (NDDs) are a heterogeneous class of conditions involving the brain, including intellectual disability and autism spectrum disorder (ASD), that affect about 1–3% of children (Miller et al, 2010). Possible explanation for the observed inconsistency of genotype-phenotype correlation may involve complex interactions of potentially pathogenic CNVs with additional/secondary CNVs, or single nucleotide variants, that could act together to determine a disease state (Velinov, 2019). According to this hypothesis, additive effects of CNVs were for instance reported in probands carrying 16p11.2 deletions and secondary CNVs that disrupt genes associated with autism and/or intellectual disability (Girirajan et al, 2010; Duyzend et al, 2016)

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