[Clinical features and molecular pathogenesis of neurodevelopmental disorder with impaired speech and hyperkinetic...

Objective: To investigate the clinical features and elucidate the molecular pathogenesis of neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM) associated with zinc finger protein 142 (ZNF142) gene variants. Methods: A retrospective case series analysis was performed. The clinical data were collected on 2 children diagnosed with NEDISHM at Children's Hospital of Nanjing Medical University in February 2025. Whole-exome sequencing (WES) was conducted to identify pathogenic variants, subsequently validated by Sanger sequencing. Variant pathogenicity was assessed using computational predictors (SIFT, PolyPhen-2, MutationTaster) and structural modeling (PyMOL). Relative quantification of ZNF142 gene transcript levels was performed using real-time quantitative PCR, with expression values normalized against 2 rigorously age-and sex-matched healthy control subjects (normalized to 1.000). Results: Two monozygotic twin males aged 7 years and 3 months. Case 1 exhibited severe language impairment, moderate intellectual disability, attention deficits, hyperactivity, impulsivity, aggressive behavior, frontal bossing, and a flat nasal bridge. Case 2 presented with mild speech disorders, mild intellectual disability, while maintaining comparable craniofacial characteristics. WES revealed compound heterozygous ZNF142 gene variants in both affected individuals (NM_001105537.4): a paternally inherited nonsense variation (c.4030C>T, p.Arg1344Ter) and a de novo missense variation (c.1271C>T, p.Thr424Met). The latter, unreported previously, was predicted as pathogenic by in silico tools and structural analysis, demonstrating hydrogen bond disruption and altered thermodynamic stability. Quantitative PCR analysis showed relative expression level of ZNF142 gene mRNA in 2 cases were 0.230 and 0.173. Conclusions: Compound heterozygous variations of the ZNF142 gene can lead to the down-regulation of ZNF142 expression and thereby result in NEDISHM. Despite having exactly same genetic background, identical twin patients with NEDISHM still show significant clinical phenotypic heterogeneity.