ZNF526 – Dentici-Novelli Neurodevelopmental Syndrome

The ZNF526 gene, which encodes a Kruppel-type zinc finger protein involved in transcriptional regulation, has been recently implicated in Dentici-Novelli neurodevelopmental syndrome. This disorder is characterized by global developmental delay, microcephaly, and seizures, conditions that warrant a thorough genetic evaluation when encountered in clinical practice (PMID:40197775). The emerging evidence from case reports and literature reviews underscores the clinical relevance of ZNF526 variants in patients with neurodevelopmental impairments.

The association is supported by autosomal recessive inheritance, as illustrated by a compound heterozygous state in the affected child. In the highlighted case, one variant was inherited from the mother while the second variant was de novo, establishing a genetic mechanism consistent with recessive transmission (PMID:40197775). Although segregation data beyond the proband are limited, the family history and mode of allele transmission help direct the diagnostic process.

Genetic evidence is bolstered by the observation of multiple patients harboring unique variants in ZNF526. Specifically, the variant c.1513T>C (p.Cys505Arg) was identified and is representative of the mutational spectrum observed across the literature. Across studies, a total of 12 cases with 11 unique variants have been reported, supporting a robust contribution of loss-of-function events to the disease phenotype (PMID:40197775).

In-depth analysis of the variant spectrum reveals that loss‑of‑function mutations, including frameshift and missense changes affecting critical protein domains, are consistently observed. The recurrence of variants such as c.1513T>C (p.Cys505Arg) in independent studies strengthens the clinical association and provides a valuable marker for molecular diagnostic assays. This finding is particularly important for laboratories developing targeted panels for neurodevelopmental disorders.

Functional assessments further substantiate the pathogenicity of ZNF526 variants. A three‑dimensional protein model employed in the study predicts that these mutations cause significant alterations to protein structure, likely leading to impaired transcriptional regulation. Such experimental data align with the clinical observations, thereby reinforcing the causal inference between mutation and disease (PMID:40197775).

The integration of genetic and experimental data, including the identification of compound heterozygous variants and supportive in silico modeling, culminates in a coherent narrative that endorses the diagnostic utility of ZNF526 testing. While additional cases and extended family studies could further elevate the scoring, current evidence sufficiently supports a moderate level of clinical validity for the gene‑disease association.

Key take‑home: Precise genetic testing for ZNF526 variants, particularly using markers such as c.1513T>C (p.Cys505Arg), is imperative for confirming Dentici‑Novelli neurodevelopmental syndrome, thereby enhancing diagnostic decision‑making and guiding informed family counseling.

References

• Molecular genetics & genomic medicine • 2025 • Novel Compound Heterozygous Variants in ZNF526 Causing Dentici-Novelli Neurodevelopmental Syndrome: A Case Report and Literature Review PMID:40197775

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