Compound heterozygous ZNF335 variants in a patient with microcephaly, refractory epilepsy, and severe developmental delay: A case report and literature review

ZNF335 plays an essential role in the neurogenesis of the human brain, and pathogenic variants of ZNF335 are associated with primary or secondary (postnatal) microcephaly. We performed exome sequencing in a patient with secondary microcephaly, epilepsy, global developmental delay, and dysmorphic craniofacial features, and identified compound heterozygous missense and intronic variants in ZNF335 (NM_022095.4:c.1504T>G, p.(Tyr502Asp) and c.1665 + 6T>A). Using a minigene assay, we demonstrated that the intronic variant causes aberrant splicing, resulting in significantly reduced ZNF335 protein levels. In addition, a review of the clinical findings of previously reported 10 patients with ZNF335 variants revealed that microcephaly was present in all patients, about half of them were secondary, and epilepsy and severe developmental delay were also quite recurrent findings.