Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Ca-v) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Ca-v genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Ca(v)3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Ca(v)3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background.

Automated summary

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. Voltage-gated calcium channels (VGCCs or Ca-v) genes, specifically the CACNA1H gene, have been identified as potential susceptibility genes for ASD. Through whole genome sequencing analysis, this study found rare damaging variants in Ca-v genes, including biallelic rare damaging missense variants in the CACNA1H gene, in ASD families. Electrophysiological analysis showed that these variants mildly affect calcium channel activity, potentially leading to dysregulation of intracellular calcium ions homeostasis and contributing to ASD etiology. These findings provide further evidence for the involvement of CACNA1H in neurodevelopmental disorders and suggest the importance of rare variants in ASD development.