CACNA2D2 encodes the alpha-2 and delta-2 auxiliary subunits of the voltage-dependent calcium channel.
To date, there have been two reports of individuals with early-infantile epileptic encephalopathy due to CACNA2D2 variants [2, 3].
Here, we describe an individual with epileptic encephalopathy and compound heterozygous missense variants in CACNA2D2. Unlike previous reports, this individual was not homozygous for any CELSR3 variants.
During reanalysis of the WES, it was noted that the proband carried two rare missense variants in the CACNA2D2 gene (p.Pro261Leu and p.Leu1046Pro), which were inherited on separate alleles (Figures 1(c) and 1(d)).
The CACNA2D2 variants were annotated according to RefSeq accessions NM_006030.2 and NP_006021.2.
The two CACNA2D2 variants identified during WES reanalysis are classified as variants of uncertain significance according to the ACMG-AMP classification criteria ; however, there are several lines of evidence to suggest these variants contribute to disease.
Of note is the consistent observation of cerebellar atrophy (Figure 1(a)), which is also reported in several mouse models of Cacna2d2 dysfunction [6, 7].
Furthermore, the observed phenotypic similarities amongst the affected individuals indicate that altered CACNA2D2 function is the cause of disease.
The mechanism by which CACNA2D2 dysfunction has been proposed to cause disease involves reduced [[alpha].sub.2][delta]2 expression and/or function, leading to reduced [[alpha].sub.1] cell surface expression and function , which is consistent with the partial clinical overlap observed between CACNA2D2- and CACNA1A-related disorders.
In conclusion, we present the third report of a patient with epileptic encephalopathy and cerebellar atrophy due to recessive variants in CACNA2D2. Importantly, we present the first case with compound heterozygous CACNA2D2 variants and no additional candidate disease variants (e.g., CELSR3), further supporting the relationship between pathogenic CACNA2D2 variants and epileptic encephalopathy with cerebellar atrophy.
Several SNPs in genes involved with ion transport have been associated with blood pressure (e.g., ATP2B1, CACNA1D, CACNA2D2
, CACNB2, KCNK3, SLC4A7, and SLC39A8; Table 1).