KCNJ8 – hypertrichotic osteochondrodysplasia Cantu type

Two unrelated patients with Cantú syndrome harbor de novo heterozygous missense variants in KCNJ8, in the absence of ABCC9 mutations. Patient 1 carried c.193G>A (p.Val65Met) and Patient 2 carried c.526T>A (p.Cys176Ser), both presenting hypertrichosis, macrosomia, osteochondrodysplasia, macrocephaly, coarse facial features, and cardiomegaly (PMID:24176758; PMID:24700710). No additional affected relatives were reported, and both variants were confirmed absent in ABCC9‐negative Cantú syndrome cohorts.

Functional assays of the Kir6.1[p.Cys176Ser] variant coexpressed with SUR1 or SUR2A demonstrate a significant gain of channel function due to reduced ATP inhibition, recapitulating the pathophysiology of Cantú syndrome and corroborating a dominant‐active mechanism (PMID:24700710). There are no published reports contradicting KCNJ8’s role in this phenotype.

Key take-home: Heterozygous gain-of-function KCNJ8 mutations cause autosomal dominant Cantú syndrome and should be included in diagnostic genetic testing panels.

References

• European Journal of Medical Genetics | 2013 | Mutation of KCNJ8 in a patient with Cantú syndrome with unique vascular abnormalities – support for the role of K(ATP) channels in this condition PMID:24176758
• Human Mutation | 2014 | Cantú syndrome resulting from activating mutation in the KCNJ8 gene PMID:24700710

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