Out of 12 patients so far reported in the literature, six carried homozygous LOF variants, four had homozygous missense variants, and two had compound heterozygous variants.
ZNF526(OMIM: 614387) is a ubiquitously expressed gene with only one long coding exon and encoding for a member of Krüppel-type zinc-finger proteins, one of the largest families of transcriptional regulators in the human genome. This gene includes 13 zinc-finger domains and, although its exact role in human development has not yet been elucidated, it is likely involved in transcriptional regulation. As a transcription factor, exhibits highly variable phenotypic impacts; functional impairment can yield diverse outcomes depending on which cellular processes are affected.
It has been observed that nonsense or frameshift variants in biallelic states are more likely to cause severe DENNED, whereas homozygous missense variants tend to present with milder, non-syndromic ID. Moreover, patients with compound heterozygous frameshift and missense variants had more severe neurodevelopmental disorders, seizures, and MRI abnormalities. LOF variants particularly predispose individuals to epilepsy, which, along with brain MRI abnormalities, exacerbates intellectual and developmental delays, suggesting LOF variants may lead to developmental and epileptic encephalopathies (DEE). In contrast, homozygous missense variants often result in non-syndromic ID, which may be under-recognized. Further patients' data and functional experiments are needed, but current findings suggest that ZNF526's genotype–phenotype relationship is complex, and potentially influenced by modifier genes, developmental conditions, and environmental factors.
ZNF526