A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (NEDASB) is caused by heterozygous mutation in the NOVA2 gene (601991) on chromosome 19q13.

Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (NEDASB) is an early-onset neurologic disorder characterized by global developmental delay, poor or absent speech and language development, and behavioral abnormalities reminiscent of autism spectrum disorder (ASD; 209850) or Angelman syndrome (AS; 105830). Additional features may include poor overall growth with small head circumference, axial hypotonia, spasticity, and seizures. Some patients have abnormal findings on brain imaging, including cerebral atrophy, cerebellar atrophy, and/or thin corpus callosum (summary by Mattioli et al., 2020).

Mattioli et al. (2020) reported 6 unrelated patients, ascertained through the collaborative efforts of several international diagnostic laboratories or research centers performing exome sequencing in patients with intellectual disability, who carried de novo heterozygous frameshift mutations in the NOVA2 gene. Five patients were between 3 and 9 years of age, and 1 was 22 years old; none had a family history of a similar disorder. These individuals presented in the first months or years of life with global developmental delay, delayed motor milestones, hypotonia, and/or feeding difficulties. Most achieved walking by age 4 years, although 1 was unable to walk at age 9, and all had impaired intellectual development with poor or absent speech and language acquisition. Behavioral abnormalities were common: most patients had autistic features, including stereotypic movements, body rocking, and poor social interaction, and several demonstrated inappropriate laughter and/or hand flapping, suggestive of Angelman syndrome. More variable features included spasticity, hyperreflexia, and/or ataxic gait. Two patients had seizures: myoclonic seizures in 1 and refractory myoclonic/absence seizures in the other. All patients had poor overall growth with borderline or small head circumference (-1 to -2.5 SD), and a few had mild dysmorphic features, such as brachycephaly, deep-set eyes, downslanting palpebral fissures, downturned mouth, anteverted nares, and deep philtrum. Two patients had normal brain imaging, but the others showed variable structural abnormalities, including thin corpus callosum, cortical atrophy, white matter loss, cerebellar volume loss, and type 1 Chiari malformation.

The heterozygous mutations in the NOVA2 gene that were identified in patients with NEDASB by Mattioli et al. (2020) occurred de novo.

In 6 unrelated patients with NEDASB, Mattioli et al. (2020) identified de novo heterozygous frameshift mutations in the NOVA2 gene (601991.0001-601991.0006). The mutations, which were found by exome sequencing through different laboratories, were not found in public databases, including gnomAD. All the mutations occurred in the last exon, exon 4, and were predicted to escape nonsense-mediated mRNA decay (NMD), although studies of patient cells were not performed. Expression of 1 of the mutations (Mut1) (601991.0001) in HeLa cells showed that the mutant protein was expressed at normal levels and showed normal nuclear localization, consistent with escape from NMD. All the mutations, which clustered near one another, resulted in frameshifts leading to the same alternative frame, and the resulting truncated proteins shared a common region of 133 residues before premature termination between residues 394-401. The full-length protein contains 492 residues. The mutations were predicted to remove the third KH domain (residues 406-473), which binds RNA loops composed of the tetranucleotide YCAY. SiRNA-mediated knockdown of NOVA2 in human neuronal cells resulted in an increase in the proportion of cells with multiple neurites and a decrease in the proportion of undifferentiated cells compared to controls. The abnormalities in neurite outgrowth could be rescued by wildtype NOVA2, but not by the Mut1 mutation. Transcriptome analysis of human neural stem cells treated with siRNA causing a 50% reduction in NOVA2 expression showed that a set of genes had differences in alternative splicing. Gene ontology analysis showed that the affected genes were related to transmembrane proteins, the extracellular matrix, cytoskeleton organization, and neuron projection/dendrite development. Genes affected included several that have been shown to undergo alternative splicing in the mouse cortex, such as SGCE (604149), NEO1 (601907), SORBS1 (605264), and DAB1 (603448). In vitro studies showed that Mut1 had a reduction in RNA binding capacity for the YCAY motif compared to wildtype, and expression of Mut1 in HeLa cells resulted in abnormal regulation of splicing of certain genes, although the findings were more consistent with a partial loss of function than a complete loss of function. There was no evidence of a dominant-negative effect.

Mattioli et al. (2020) found that knockdown of the nova2 ortholog (nova1a) in zebrafish resulted in a reduction in the number of axonal tracts formed between optic tecta, as well as a reduction in tecta size. The morpholino phenotype could be rescued by wildtype NOVA2 mRNA, but not by NOVA2 mutant (Mut1) mRNA. However, injection of either wildtype or Mut1 NOVA2 alone did not significantly affect axonal tracts.