ZNF142 – Neurodevelopmental Disorder with Impaired Speech and Hyperkinetic Movements

Recent case reports and multi‐patient studies robustly link biallelic loss‐of‐function variants in ZNF142 with a neurodevelopmental disorder characterized by impaired speech, moderate intellectual disability, global developmental delay, and seizures (PMID:35618198, PMID:38655717). In several independent families – including an Iranian family with compound heterozygous variants and a case series of three affected siblings – segregation analyses confirmed that the identified variants co‐segregate with the disorder, highlighting a clear autosomal recessive inheritance pattern (PMID:37496384).

Genetic evidence is strengthened by the recurrent observation of a truncating variant, c.25C>T (p.Gln9Ter), which has been reported across multiple studies and is consistent with a loss‐of‐function mechanism. Additional reports documenting various mutation types (missense, frameshift, and truncating variants) across at least six unrelated families further substantiate the gene–disease relationship (PMID:35618198).

Functional assessment studies have provided critical experimental insights. Knock‑in mouse models and in vitro analyses replicate core features of the human phenotype and demonstrate that ZNF142 disruption leads to impaired transcriptional regulation and neurodevelopmental anomalies. These results support a pathogenic mechanism due to haploinsufficiency and are concordant with the segregation and genetic data (PMID:35616059, PMID:38296634).

Some reports also highlight potential sex‐dependent expressivity and variable facial dysmorphism; however, the primary neurological and developmental impairments remain consistent, thereby reinforcing the clinical validity of the association.

The aggregated genetic and functional evidence, derived from a diversity of study designs and cohorts, positions the ZNF142–neurodevelopmental disorder association in the strong ClinGen category. This conclusion is supported by multiple unrelated probands, clear familial segregation, and functional models that recapitulate the human disease phenotype.

Clinically, this evidence underscores the utility of including ZNF142 in diagnostic panels for patients presenting with speech impairment, intellectual disability, and hyperkinetic movements, thereby aiding in precise diagnosis and genetic counseling.

Key Take‑home: Robust genetic and experimental evidence firmly establish ZNF142 as a critical gene in the pathogenesis of neurodevelopmental disorder with impaired speech and hyperkinetic movements.

References

• European journal of medical genetics • 2022 • ZNF142 mutation causes neurodevelopmental disorder with speech impairment and seizures: Novel variants and literature review PMID:35618198
• Molecular genetics & genomic medicine • 2023 • A deleterious frameshift insertion mutation in the ZNF142 gene leads to intellectual developmental disorder with impaired speech in three affected siblings: Clinical features and literature review PMID:37496384
• American journal of medical genetics. Part A • 2024 • A case report of a patient with neurodevelopmental disorder with impaired speech and hyperkinetic movements: A biallelic variant in the ZNF142 gene PMID:38655717
• Clinical genetics • 2022 • Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder PMID:35616059
• Journal of medical genetics • 2024 • ZNF142 mutation causes sex‑dependent neurologic disorder PMID:38296634

Evidence Based Scoring (AI generated)