CAMK2D

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:1040008

Submitter: ClinGen

*CAMK2D* was first reported in relation to autosomal dominant *CAMK2D*-related neurodevelopmental disorder and dilated cardiomyopathy in 2024 (Rigter et al., PMID: 38272033). *CAMK2D* encodes a member of the family of type II multifunctional calcium- and calmodulin-dependent protein kinases, which play a central role in synaptic plasticity, learning, and memory. *CAMK2D* is the major CAMK2 isozyme present in the heart and plays an important role in cardiac function. Affected individuals present with speech and motor delays, intellectual disability (mild to profound), dysmorphic facial features, behavioral abnormalities (including autism spectrum disorder), skeletal abnormalities, brain MRI anomalies, and dilated cardiomyopathy often requiring cardiac transplantation (PMIDs: 37372357, 38272033). Additional features in a subset of individuals can include seizures, visual abnormalities, digestive problems (including tube feeding), and kidney abnormalities. Six missense variants reported in 8 probands in 3 publications (PMIDs: 27479843, 37372357, 38272033) are included in this curation, with most variants arising *de novo*. One recurrent variant, p.Arg275His, has been reported in at least 3 families, 2 of which are scored in this curation (PMIDs: 27479843, 37372357, 38272033). The third family includes a set of 3 siblings with dilated cardiomyopathy; 2 of these siblings also have neurodevelopmental disorders and a 16p11.2 microdeletion (PMID: 38272033). Their father, deceased at the time of the report (and therefore unavailable for testing), also had a history of dilated cardiomyopathy. While not scored due to the compounding 16p11.2 microdeletion, the presence of dilated cardiomyopathy within this family lends additional support to the assertion that variation in this gene causes cardiac phenotypes in addition to neurodevelopmental disorders. Functional assays assessing protein levels, kinase activity, and impact on neuronal migration of these patient-specific *CAMK2D* missense variants demonstrated both gain-of-function and loss-of-function effects, with only gain-of-function variants proposed to be associated with the cardiac phenotype (PMID: 38272033). However, more evidence is needed to determine a specific phenotype correlation with disease mechanism. *CAMK2D* is constrained for missense (Z = 3.41, gnomAD v4.1.1) but not loss-of-function variants (pLI = 0.02, LOEUF = 0.58). One individual with a *de novo* splice variant predicted to lead to a frameshift was not scored for this reason. This gene-disease relationship is also supported by experimental evidence, including biochemical function, protein interactions, and mouse knockdown, overexpression and rescue models (PMID: 38272033). The 3 other members of the CAMK2 family, *CAMK2A*, *CAMK2B*, and *CAMK2G*, are also involved in neurodevelopmental disorders (PMID: 39631163), and form homo- and hetero-oligomeric complexes with CAMK2D. In summary, there is strong evidence supporting the relationship between *CAMK2D* and autosomal dominant *CAMK2D*-related neurodevelopmental disorder and dilated cardiomyopathy. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 15, 2025 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:1040008

Submitter: G2P