Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy

摘要

CACNA1C (NM_000719.6) encodes an L-type calcium voltage-gated calcium channel (Ca(v)1.2), and pathogenic variants have been associated with two distinct clinical entities: Timothy syndrome and Brugada syndrome. Thus far, CACNA1C has not been reported as a gene associated with epileptic encephalopathy and is less commonly associated with epilepsy. We report three individuals from two families with variants in CACNA1C. Patient 1 presented with neonatal onset epileptic encephalopathy (NOEE) and was found to have a de novo missense variant in CACNA1C (c.4087GA (p.V1363M)) on exome sequencing. In Family 2, Patient 2 presented with congenital cardiac anomalies and cardiomyopathy and was found to have a paternally inherited splice site variant, c.3717+1_3717+2insA, on a cardiomyopathy panel. Her father, Patient 3, presented with learning difficulties, late-onset epilepsy, and congenital cardiac anomalies. Family 2 highlights variable expressivity seen within a family. This case series expands the clinical and molecular phenotype of CACNA1C-related disorders and highlights the need to include CACNA1C on epilepsy gene panels.