KCNK9 – Birk-Barel syndrome

Birk-Barel syndrome, also known as KCNK9 imprinting syndrome, is a rare maternally inherited neurodevelopmental disorder characterized by congenital hypotonia, global developmental delay, intellectual disability, feeding difficulties, craniofacial dysmorphism, and occasional peripheral motor neuropathy. KCNK9 encodes the TASK3 two-pore-domain potassium channel, and pathogenic missense variants disrupt channel conductance and regulation, leading to neuronal migration defects and altered neural excitability (PMID:24342771, PMID:35698242).

Genetic evidence supports an autosomal dominant inheritance pattern with maternal expression of KCNK9. A cohort study described 47 unrelated affected individuals harboring 15 distinct KCNK9 variants, including a recurrent hotspot c.706G>A (p.Gly236Arg) and novel variants such as c.710C>A (p.Ala237Asp) (PMID:35698242). Three additional independent case reports—one adolescent with pure motor neuropathy bearing c.710C>A (p.Ala237Asp) (PMID:30690205), one neonate with severe obstructive sleep apnea (PMID:37358997), and one multidisciplinary surgical case (PMID:35949010)—further extend the variant spectrum.

Segregation analysis confirms maternal transmission in multiple families, consistent with imprinting, although precise counts of additional affected relatives are limited. Case reports uniformly describe de novo or maternally inherited missense variants in affected probands, with absence of these changes in healthy controls.

Phenotypic spectrum includes neonatal hypotonia and feeding problems, global developmental delay, intellectual disability, speech and motor delays, hypotonia, scoliosis, laryngomalacia, dysphonia, dysphagia, and craniofacial features such as micrognathia, cleft palate, dolichocephaly, broad nasal tip, and broad philtrum (PMID:30690205, PMID:35949010, PMID:37358997).

Functional studies demonstrate that the p.Gly236Arg variant reduces outward TASK3 currents and alters rectification and sensitivity to regulators compared with wild-type channels; these defects can be partially rescued by secondary mutations (A237T) or pharmacologic activation with flufenamic acid (PMID:24342771). Knockdown of KCNK9 in mouse cortical neurons impairs neuronal migration via an activity-dependent mechanism that is rescued by RNAi-resistant wild-type KCNK9 but not by dominant-negative mutants (PMID:23236211). Recent electrophysiologic and computational modeling of novel variants reveal both gain- and loss-of-function effects with consistent impairment of channel regulation (PMID:35698242).

No credible conflicting evidence has been reported; screening of 120 intellectual disability, 86 autism spectrum disorder, and 86 Tourette syndrome patients identified no pathogenic KCNK9 variants or imprinting disturbances outside of Birk-Barel syndrome (PMID:24980697).

Integration of genetic and experimental data supports a strong gene-disease association under an autosomal dominant imprinting model. KCNK9 sequencing is recommended for individuals with suggestive neurodevelopmental and craniofacial phenotypes, and functional variant data inform potential targeted therapies to modulate TASK3 activity. Key take-home: Pathogenic KCNK9 variants cause Birk-Barel syndrome through disrupted TASK3 channel function, enabling precision diagnosis and tailored therapeutic exploration.

References

• European Journal of Medical Genetics • 2020 • Novel variant in the KCNK9 gene in a girl with Birk Barel syndrome. PMID:30690205
• Frontiers in Medicine • 2023 • A rare early-onset neonatal case of Birk-Barel syndrome presenting severe obstructive sleep apnea: a case report. PMID:37358997
• The Journal of Craniofacial Surgery • 2023 • Birk-Barel Intellectual Disability Dimorphism and KCNK9 Imprinting Syndrome: Craniofacial Surgery Considerations for an Exceedingly Rare Syndrome. PMID:35949010
• Genome Medicine • 2022 • Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome. PMID:35698242
• Molecular Pharmacology • 2014 • Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. PMID:24342771
• Cerebral Cortex • 2014 • Dysfunction of KCNK potassium channels impairs neuronal migration in the developing mouse cerebral cortex. PMID:23236211
• American Journal of Medical Genetics Part B • 2014 • Screening individuals with intellectual disability, autism and Tourette's syndrome for KCNK9 mutations and aberrant DNA methylation within the 8q24 imprinted cluster. PMID:24980697

Evidence Based Scoring (AI generated)