Language

English

Publication Date

2-1-2024

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2023.12.016

PMID

38272033

PMCID

PMC10870144

PubMedCentral® Posted Date

1-24-2024

PubMedCentral® Full Text Version

Post-print

Abstract

The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.

Keywords

Animals, Humans, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cardiomyopathy, Dilated, Heart, Intellectual Disability, Neurodevelopmental Disorders, calcium/calmodulin-dependent protein kinase 2 delta, CAMK2D, intellectual disability, cardiomyopathy, neurodevelopment

Comments

This article has been corrected. See Am J Hum Genet. 2025 Aug 11;112(9):2247.

Published Open-Access

yes

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