CAMK2D De Novo Missense Variant in Patient with Syndromic Neurodevelopmental Disorder: A Case Report

Abstract

Background: Intellectual disability with developmental delay is the most common developmental disorder. However, this diagnosis is rarely associated with congenital cardiomyopathy. In the current report, we present the case of a patient suffering from dilated cardiomyopathy and developmental delay.

Methods: Neurological pathology in a newborn was diagnosed immediately after birth, and the acquisition of psychomotor skills lagged behind by 3-4 months during the first year of life. WES analysis of the proband did not reveal a causal variant, so the search was extended to trio.

Results: Trio sequencing revealed a de novo missense variant in the CAMK2D gene (p.Arg275His), that is, according to the OMIM database and available literature, not currently associated with any specific inborn disease. The expression of Ca²⁺/calmodulin-dependent protein kinase II delta (CaMKIIδ) protein is known to be increased in the heart tissues from patients with dilated cardiomyopathy. The functional effect of the CaMKIIδ Arg275His mutant was recently reported; however, no specific mechanism of its pathogenicity was proposed. A structural analysis and comparison of available three-dimensional structures of CaMKIIδ confirmed the probable pathogenicity of the observed missense variant.

Conclusions: We suggest that the CaMKIIδ Arg275His variant is highly likely the cause of dilated cardiomyopathy and neurodevelopmental disorders.

Keywords: CAMK2D; Ca2+/calmodulin-dependent protein kinase II delta; WES; dilated cardiomyopathy; neurodevelopmental disorder; trio; whole exome sequencing.

Figure 5

(a) Autoinhibited state of CaMKIIδ (PDB ID 2vn9). The inhibitory αI helix is shown in red. Ala279 forms a hydrogen bond with Arg275, which may facilitate the binding of the adjacent αI helix. (b) Ca²⁺/calmodulin-bound state of CaMKIIδ (PDB ID 2wel). Ala279 is displaced with the Arg275 side chain and located at an unfolded region. The Arg275His substitution, shown in yellow, was modeled with Swiss-PdbViewer [20]. Missing residues 277–280 of the unfolded region were constructed with RCD+ [21]. The figure was prepared using VMD [22].

Figure 1

Fetal cardiothoracic ratio: 31 weeks of gestation.

Figure 2

Phenotypic features at the age of 8 months of life. (a,b) Frontal bossing, underfolded cleft helix, prominent superior crus of antihelix, serpiginous left antihelix stem. The parents granted permission to publish their child’s photographs.

Figure 3

Echocardiography picture of the left ventricle at the age of 3 years (M-mode): EDVT = 139.96 mL, ESVT = 73.08 mL, SV = 66.88 mL, EF = 47.79%, FS = 24.26%, HR = 82(2) Bpm. The white numbers indicate the systolic and diastolic cardiac cycle.

Figure 4

(a) Variant shown in IGV viewer in the proband reads and absent in the parent samples; (b) trio Sanger sequencing.