CAMK2B – Intellectual Disability, Autosomal Dominant 54

Calcium/calmodulin-dependent protein kinase II β (CaMKIIβ), encoded by CAMK2B, is a serine/threonine kinase critical for synaptic plasticity, learning, and memory. Heterozygous de novo variants in CAMK2B cause a neurodevelopmental disorder (MRD54) characterized by delayed psychomotor development, mild to severe intellectual disability, hypotonia, and behavioral abnormalities (PMID:37391113). Inheritance is autosomal dominant with virtually all pathogenic variants arising de novo.

Genetic evidence includes nine unrelated probands harboring de novo CAMK2B variants in a multi-center cohort (PMID:29100089), two additional de novo CAMK2B cases identified in a separate neurodevelopmental cohort (PMID:29560374), and one detailed case report (PMID:35620293), totaling 12 unrelated individuals. A representative variant is c.709G>A (p.Glu237Lys). No instances of familial segregation have been reported.

The variant spectrum comprises seven missense substitutions (including p.Glu237Lys) and five loss-of-function or splice-site variants (c.1310del (p.Pro437fs), c.863_864del (p.Val288fs), c.85C>T (p.Arg29Ter), c.903+1G>A, c.820-1G>A) with no recurrent or founder alleles described. Allele frequencies in public databases are exceedingly low or absent.

Functional studies demonstrate that CAMK2B missense variants alter Thr287 autophosphorylation, impacting kinase activation and neuronal migration in vitro (PMID:29100089). Electrophysiological assays in mutant neurons reveal increased A-type K⁺ currents and altered inhibitory long-term potentiation (PMID:29560374). A de novo p.Glu110Lys gain-of-function variant leads to neuropsychiatric episodes responsive to therapies modulating CAMKII activity (PMID:35620293).

No studies have refuted or significantly disputed the CAMK2B–MRD54 association. The consistency of de novo occurrence, variant clustering in functional domains, and concordant experimental data establish a robust gene–disease relationship.

Together, the genetic and functional data support a Strong classification of CAMK2B in autosomal dominant intellectual disability (MRD54). Key Take-home: De novo CAMK2B variants cause autosomal dominant intellectual disability with hypotonia, supported by convergent molecular and electrophysiological evidence, guiding accurate diagnosis and informing targeted therapeutic strategies.

References

• Neuroscience and Biobehavioral Reviews • 2023 • Understanding the pathogenetic mechanisms underlying altered neuronal function associated with CAMK2B mutations. PMID:37391113
• American Journal of Human Genetics • 2017 • De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. PMID:29100089
• Annals of Clinical and Translational Neurology • 2018 • De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders. PMID:29560374
• Frontiers in Pharmacology • 2022 • Case Report: Developmental Delay and Acute Neuropsychiatric Episodes Associated With a de novo Mutation in the CAMK2B Gene (c.328G>A p.Glu110Lys). PMID:35620293

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