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KCNH1 encodes a voltage‑gated potassium channel that plays a critical role in neuronal development and function. Multiple studies have established its involvement in Zimmermann‑Laband Syndrome (ZLS), a disorder characterized by gingival overgrowth, gingival fibromatosis, nail hypoplasia/aplasia, and distinctive craniofacial features. The convergence of genetic and functional evidence has led to a robust gene‑disease assertion for KCNH1 in ZLS.
A recent case report described a 2‑year‑old patient presenting with marked gingival enlargement and hypoplastic nails. Whole‑exome sequencing revealed a de novo pathogenic variant, c.2198C>T (p.Pro733Leu), which has been confirmed by Sanger sequencing (PMID:39087232). This case, along with other sporadic reports, underscores the autosomal dominant inheritance pattern typical of ZLS caused by KCNH1 mutations.
In multi‑patient studies, additional de novo missense variants in KCNH1 were identified in individuals with overlapping phenotypes that include intellectual disability, abnormal facial dysmorphism, and gingival anomalies (PMID:26264464). These reports provide further confirmation that KCNH1 mutations consistently segregate with the disorder and contribute to the phenotypic spectrum of ZLS.
Functional studies support a gain‑of‑function mechanism for KCNH1 variants in ZLS. In vitro patch‑clamp recordings and cellular assays have demonstrated that these mutations lead to altered channel activation properties, thereby disrupting normal cellular excitability (PMID:25915598). Such experimental data strongly reinforce the pathogenic role of KCNH1 in ZLS.
Integrating the genetic and functional evidence, the association between KCNH1 and Zimmermann‑Laband Syndrome is firmly supported. The totality of the evidence—including multiple independent de novo variants and concordant functional assessments—provides high clinical utility for diagnostic decision‑making.
Key take‑home: Targeted genetic testing for KCNH1 variants is essential in patients with clinical features of ZLS, enabling early diagnosis and tailored clinical management.
Gene–Disease AssociationStrongMultiple independent de novo reports and corroborative multi‑patient studies (e.g., 2+ separate studies with several probands PMID:39087232, PMID:26264464) support a strong gene‑disease association. Genetic EvidenceStrongAt least one clearly defined de novo pathogenic variant, c.2198C>T (p.Pro733Leu), has been identified in a patient with ZLS, with additional reports of KCNH1 variants in independent cases confirming the association (PMID:39087232). Functional EvidenceStrongPatch‑clamp recordings and other cellular assays demonstrate that ZLS‑associated KCNH1 missense variants lead to a gain‑of‑function effect, aligning with the observed clinical phenotype (PMID:25915598). |