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The association between ZNF462 and metopic ridging-ptosis-facial dysmorphism syndrome is supported by multiple independent case reports and multi‐patient studies demonstrating autosomal dominant inheritance. Several studies have identified heterozygous loss‑of‑function variants, including the recurrent c.3306dup (p.Gln1103ThrfsTer10) variant, in patients presenting with characteristic craniofacial dysmorphism, developmental delay, and additional features such as epicanthus and ptosis (PMID:32543299). The reported cases include both de novo events as well as familial segregation with affected relatives showing a consistent phenotype, thereby strengthening the gene‑disease link.
Genetic evidence from case series indicates that over 40 affected individuals have been documented with variants in ZNF462. In several reports, detailed segregation analyses have revealed that affected relatives, including parent–child pairs, share the pathogenic variant, supporting autosomal dominant transmission (PMID:35198003; PMID:36568367). Furthermore, the variant spectrum predominantly consists of truncating variants resulting in haploinsufficiency, which is concordant with the observed clinical features.
Functional studies provide corroborative evidence for the role of ZNF462 in craniofacial and neurodevelopment. Experimental assays, including minigene splicing analyses and in vitro functional rescue experiments, have demonstrated that loss‑of‑function of ZNF462 disrupts normal transcriptional regulation and chromatin remodelling during embryogenesis (PMID:39069253). Animal models engineered to mimic these truncating mutations recapitulate key aspects of the human phenotype, underscoring the pathogenic mechanism of haploinsufficiency.
The integrated evidence from genetic and experimental studies supports a strong clinical validity for the association between ZNF462 and metopic ridging-ptosis-facial dysmorphism syndrome. Although additional modifiers may contribute to phenotypic variability, the recurrence of loss‑of‑function variants, consistent segregation data, and concordant functional findings collectively justify a strong ClinGen gene‑disease association.
Additional studies beyond the ClinGen scoring maximum have further expanded the phenotypic spectrum to include features such as dysplastic corpus callosum, sensorineural hearing impairment, and growth hormone deficiency. These observations emphasize the clinical heterogeneity and the need for comprehensive genetic screening in suspected cases. Moreover, the emerging evidence calls for further collaboration to refine diagnostic criteria and build robust genotype‑phenotype correlations.
Key take‑home: The strong association of heterozygous truncating variants in ZNF462 with metopic ridging-ptosis-facial dysmorphism syndrome makes genetic testing an invaluable tool for accurate diagnosis, informed clinical management, and future therapeutic research.
Gene–Disease AssociationStrongMultiple independent case reports and multi‐patient studies report approximately 40 affected individuals with heterozygous loss‐of‐function variants in ZNF462, accompanied by robust segregation and concordant functional evidence (PMID:32543299; PMID:39501256). Genetic EvidenceStrongNumerous heterozygous truncating variants, including c.3306dup (p.Gln1103ThrfsTer10), have been identified across unrelated probands with autosomal dominant inheritance, supported by familial segregation studies (PMID:35198003; PMID:36568367). Functional EvidenceModerateFunctional assays including minigene splicing tests and animal models demonstrate that ZNF462 loss‐of‐function disrupts normal developmental processes, and rescue experiments further support the pathogenic mechanism of haploinsufficiency (PMID:39069253; PMID:39501256). |