NOVA1 – Rett syndrome

Two case reports have identified chromosomal deletions involving NOVA1 (HGNC:7886) in patients diagnosed with Rett syndrome (MONDO_0010726) (PMID:27486480, PMID:29920362). In these patients, a 4.09–5 Mb deletion at 14q12 was observed, which encompassed not only NOVA1 but also other genes such as FOXG1 and PRKD1. As FOXG1 is a well‐established cause of the congenital variant of Rett syndrome, the independent contribution of NOVA1 to the phenotype remains uncertain. The genetic evidence for NOVA1's association with Rett syndrome is therefore limited since the deletions were part of a larger genomic event and lacked independent segregation data, with no additional affected relatives reported (PMID:27486480).

Genetic evidence is further limited by the absence of a discrete, well‐characterized coding variant in NOVA1 that can be specifically linked to the clinical phenotype; the reported deletions do not yield a precise HGVS coding change suitable for variant-specific attribution. Functional studies of NOVA1, however, demonstrate its critical role in neuronal alternative splicing and RNA binding, particularly through the regulation of targets such as the GABA(A) receptor gamma2 subunit (PMID:12808107). Yet, despite robust data supporting its biological role in neural RNA processing, these assays do not provide direct evidence for a mechanistic link between NOVA1 dysfunction and the Rett syndrome phenotype.

Overall, the available data integrate genetic and functional findings to suggest that while NOVA1 is a key regulator of neuronal splicing, its association with Rett syndrome is currently supported only by limited evidence. Additional patient-specific genetic data and segregation analyses will be required to clarify whether alterations in NOVA1 contribute independently to the clinical spectrum of Rett syndrome. This case exemplifies the importance of differentiating the effect of contiguous gene deletions from that of a single-gene disorder.

Key Take‑home sentence: While NOVA1 is essential for neuronal splicing regulation, its independent clinical association with Rett syndrome remains limited and requires further investigation.

References

• Molecular cytogenetics • 2016 • Partial monosomy14q involving FOXG1 and NOVA1 in an infant with microcephaly, seizures and severe developmental delay PMID:27486480
• Gene • 2018 • Whole exome sequencing identifies a novel 5 Mb deletion at 14q12 region in a patient with global developmental delay, microcephaly and seizure PMID:29920362
• Molecular and cellular biology • 2003 • Nova regulates GABA(A) receptor gamma2 alternative splicing via a distal downstream UCAU-rich intronic splicing enhancer PMID:12808107

Evidence Based Scoring (AI generated)