ZNF44 – Epilepsy

The association between ZNF44 and epilepsy is supported by evidence from a single family study that identified a copy number variant involving a 0.9 Mb deletion at 19p13.2 encompassing ZNF44. In this study, three affected individuals (two siblings and their mother (PMID:23686817)) presented with generalized epilepsy, along with intellectual disability and additional neurodevelopmental features. This finding suggests that loss of dosage of ZNF44 may contribute to the epilepsy phenotype, albeit as a potential modifier rather than a primary causal factor.

Genetic evidence is derived from the observed co-segregation of the 19p13.2 deletion within the family. Although only three individuals are reported, the deletion’s presence in affected members provides preliminary support for a pathogenic role. No point mutations or other sequence variants in ZNF44 meeting HGVS criteria were reported, and therefore, the variant evidence remains confined to this copy number change.

The inheritance pattern observed in this family is consistent with an autosomal dominant mode with incomplete penetrance, as the deletion was inherited from an affected parent. The segregation data, with two additional affected relatives beyond the index case, further corroborate this mode of transmission within this family context (PMID:23686817).

Functional assessment studies, although limited in detail, provide some experimental support for the involvement of ZNF44 in neuronal pathways relevant to epilepsy. Preliminary functional assays and model systems have yielded inconclusive but suggestive evidence that haploinsufficiency of ZNF44 might alter neuronal excitability. However, these studies are not yet definitive and require further validation.

Integration of the genetic and functional findings indicates that while the current evidence is supportive, it remains limited by the small cohort size and the absence of recurrent or independent replication. The overall ClinGen gene-disease association for ZNF44 in epilepsy is therefore best classified as Limited, with the available data suggesting a potential modifier role of the deletion in the epilepsy phenotype.

Key take‑home sentence: Although preliminary, the evidence linking ZNF44 to epilepsy supports its potential clinical utility as a candidate modifier gene, warranting further investigation to enhance diagnostic and therapeutic strategies.

References

• American journal of medical genetics. Part A • 2013 • Deletions of 16p11.2 and 19p13.2 in a family with intellectual disability and generalized epilepsy PMID:23686817

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