KCNK4 – Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome

The two-pore domain potassium channel KCNK4 is implicated in a rare neurodevelopmental disorder characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth (FHEIG syndrome) (KCNK4; facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome). Since its initial description in 2018 with multiple de novo missense mutations causing gain-of-function channel effects (PMID:30290154), at least ten affected individuals from seven unrelated families have been reported to date.

FHEIG syndrome follows an autosomal dominant inheritance pattern with predominantly de novo occurrences. De novo missense variants in KCNK4 have been documented in eight independent probands, and the first familial segregation was confirmed in an Egyptian mother–son pair carrying c.730G>C (p.Ala244Pro) (PMID:37750049). Segregation of the variant in that single family provides supportive evidence for dominant transmission and variable expressivity.

Affected individuals (n=10) harbor exclusively missense gain-of-function alleles (six unique variants: p.Ala244Pro, p.Ala244Val, p.Ala172Glu, p.Gly139Glu, p.Gly139Arg, p.Pro233Leu), with no loss-of-function or truncating variants reported (PMID:36683851; PMID:39146707). Phenotypic features include hypertrichosis (HP:0000998), gingival overgrowth (HP:0000212), joint hypermobility (HP:0001382), seizures (HP:0001250), facial dysmorphism (HP:0000271), and atrial fibrillation (HP:0005110). Variable expressivity ranges from full-blown FHEIG syndrome to isolated hypertrichosis and gingival fibromatosis in the mother of the initial familial case.

Functional studies using patch-clamp electrophysiology and molecular dynamics simulations have consistently demonstrated gain-of-function effects of disease-associated KCNK4 mutants, including increased basal activity, impaired mechanosensitivity, and a dominant gating defect mediated by lateral intramembrane fenestrations (PMID:30290154). These assays provide concordant mechanistic evidence linking variant effects to the clinical phenotype.

No conflicting evidence has been reported to date. Collectively, genetic and experimental data support a strong clinical validity for the association between KCNK4 and FHEIG syndrome, guiding diagnostic sequencing and enabling precise genetic counseling.

Key take-home: Gain-of-function missense variants in KCNK4 cause an autosomal dominant syndrome with characteristic craniofacial, neurodevelopmental, dermatologic, and dental manifestations, for which targeted diagnosis and management strategies are now established.

References

• American Journal of Human Genetics • 2018 • Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome. PMID:30290154
• 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
• Frontiers in Molecular Neuroscience • 2022 • Expanding the phenotypic spectrum of KCNK4: From syndromic neurodevelopmental disorder to rolandic epilepsy. PMID:36683851
• American Journal of Medical Genetics Part A • 2024 • A recurrent KCNK4 variant in a dominant pedigree with hypertrichosis and gingival fibromatosis syndrome: Variable phenotypic expressivity and insights on patients' dental management. PMID:37750049
• Seizure • 2024 • The epilepsy phenotype of KCNK4-related neurodevelopmental disease. PMID:39146707

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