The NOVA2 gene encodes a neuronal RNA-binding protein that plays a crucial role in regulating alternative mRNA splicing. NOVA2 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2020 (Mattioli et al., PMID: 32197073). Affected individuals present with global developmental delay, intellectual disability, significantly impaired speech, facial dysmorphism, hypotonia, spasticity or gait ataxia, and behavioral abnormalities including autism spectrum disorder or autistic features. Some individuals exhibit behaviors reminiscent of Angelman syndrome, such as frequent laughter and attraction to water. Additional features include progressive microcephaly, seizures, and structural brain abnormalities.
Thirteen truncating variants (12 frameshift, 1 nonsense) that have been reported in 13 probands in two publications (PMIDs: 32197073, 35607920) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants were de novo in all instances in which parental DNA was available. All the frameshift variants are located in the last exon and are predicted to escape nonsense-mediated mRNA decay. Ten frameshift variants cluster between residues 237 and 276, and replace the KH3 RNA-binding domain by a similar alternative C-terminal sequence. The mechanism of pathogenicity is hypothesized to be partial loss-of-function (hypomorphic) rather than haploinsufficiency, although a possible gain-of-function effect of the new C-terminal extension cannot be excluded (PMID: 32197073).
This gene-disease relationship is also supported by experimental evidence, including mouse and zebrafish models, and functional alterations in non-patient cells.
In summary, there is definitive evidence supporting the relationship between NOVA2 and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 15, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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