August 7, 2025Open Access

ZNF496 as Candidate Gene for Neurodevelopmental Disorders: Identification of a Pathogenic De Novo Frameshift Variant

FCFrancesco Calı̀Università degli Studi di Enna Kore MVMiriam VirgillitoUniversity of Catania STSimone TreccarichiUniversity of Catania

Key Points

A de novo frameshift variant in the znf496 gene was identified in an individual with neurodevelopmental disorders.
The pathogenic variant leads to a shorter protein, potentially disrupting interactions with JARID2 and affecting target genes.
Whole-exome sequencing and computational analyses provided insights into the pathogenic effects of the identified mutation.
The discovery marks the first association of znf496 with neurodevelopmental disorders, warranting further functional studies.

Abstract

Zinc finger proteins are frequently implicated in a wide range of neurodevelopmental disorders (NDDs). In this study, we report a case of mild intellectual disability (ID), global developmental delay (GDD), and developmental coordination disorder (DCD) in an individual with unaffected parents. Trio-based whole-exome sequencing (WES) identified a de novo variant (c.1530dup, p.Glu511ArgfsTer16) in the ZNF496 gene of the proband. According to ACMG guidelines, this novel variant is classified as pathogenic. It creates a frameshift that introduces a premature stop codon, resulting in a truncated protein of 525 amino acids (compared to the wild-type 587 residues). Notably, NMDEscPredictor analysis predicted that the transcript escapes nonsense-mediated decay (NMD) despite the frameshift. Computational analyses suggest the potential pathogenetic effects of the identified variant. As documented, ZNF496 interacts with JARID2, a gene associated with NDDs, ID and facial dysmorphism (MIM: #620098). In silico analyses suggest that the identified mutation disrupts this interaction by deleting ZNF496’s C2H2 domain, potentially dysregulating JARID2 target genes. To our knowledge, this is the first reported association between ZNF496 and NDDs, and the variant has been submitted to the ClinVar database (SCV006100880). Functional studies are imperative to validate ZNF496’s role in NDDs and confirm the mutation’s impact on ZNF496-JARID2 interactions.

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