KCNN3 – Zimmermann-Laband Syndrome

Zimmermann-Laband syndrome (ZLS) is a rare, autosomal dominant potassium channelopathy characterized by gingival hypertrophy, hypertrichosis, hypoplasia of nails and terminal phalanges, coarse facial features, and variable intellectual disability. Three genes—KCNH1, KCNN3, and ATP6V1B2—are implicated in ZLS, with heterozygous missense variants in KCNN3 defining ZLS3. Clinical exome sequencing in multiple cohorts has identified de novo KCNN3 variants in individuals presenting with the classic ZLS phenotype, establishing its role in disease pathogenesis.

To date, nine probands across seven unrelated families have been reported with de novo heterozygous missense KCNN3 variants, including concordant monozygotic twins and sporadic cases (PMID:31155282; PMID:34907639; PMID:40358131). All variants are absent from population controls, affect conserved residues, and are predicted deleterious by in silico tools.

Familial segregation is documented in a monozygotic twin pair sharing a novel KCNN3 variant and concordant phenotype, providing evidence for segregation in one additional affected relative (PMID:34907639). The remaining cases represent independent de novo events, underscoring a dominant mutational mechanism.

Pathogenic KCNN3 variants are exclusively missense substitutions in the pore-forming SK3 channel. Notably, the recurrent c.1606G>A (p.Ala536Thr) variant has been identified in a sporadic ZLS3 case and expands the allelic series for this gene (PMID:40358131).

Mechanistic studies in CHO cells demonstrate that ZLS-associated KCNN3 substitutions result in SK3 gain-of-function, with increased Ca2+ sensitivity and accelerated channel activation kinetics, confirming a pathogenic gain-of-function mechanism (PMID:31155282).

Clinical variability includes hypertrichosis (HP:0000998), hypoplasia of distal phalanges (HP:0009882), coarse facial features (HP:0000271), gingival overgrowth (HP:0000212), tapered fingers (HP:0001182), and nail hypoplasia (HP:0001792). Some individuals exhibit mild neurodevelopmental phenotypes or lack gingival fibromatosis, broadening the clinical spectrum (PMID:34907639; PMID:40358131).

The confluence of robust de novo genetic evidence and concordant functional data supports a Strong ClinGen gene–disease association for KCNN3 in ZLS. Incorporation of KCNN3 into diagnostic gene panels enables accurate molecular diagnosis and informed genetic counseling. Key Take-home: SK3 gain-of-function variants in KCNN3 are a validated dominant cause of Zimmermann-Laband syndrome, guiding precision diagnosis and family planning.

References

• American Journal of Human Genetics | 2019 | Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca2+-Activated K+ Channel SK3 Cause Zimmermann-Laband Syndrome. PMID:31155282
• American Journal of Medical Genetics. Part A | 2022 | Zimmermann-Laband syndrome in monozygotic twins with a mild neurobehavioral phenotype lacking gingival overgrowth-A case report of a novel KCNN3 gene variant. PMID:34907639
• American Journal of Medical Genetics. Part A | 2025 | Absence of Neurodevelopmental Impairment in an Individual With KCNN3-Related Zimmermann Laband Syndrome. PMID:40358131

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