Abstract
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 Cav) 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 Cav 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 Cav3.2 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 Cav3.2 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.
Highlights
Autism Spectrum Disorder (ASD) is a group of clinically heterogeneous neurodevelopmental disorders with a prevalence of >1% [1], characterized by impairments in communication and social interaction, and the presence of repetitive and restrictive behaviors [2].ASD is a multifactorial disorder, with a strong genetic component and an estimated heritability of 60–90% [3, 4]
In order to investigate the contribution of voltage-gated calcium channels (VGCCs) to ASD, we analyzed the sequence of the whole genome in a cohort of 105 families comprising 124 individuals with a diagnosis of ASD, and we looked for rare coding damaging variants in genes encoding for VGCCs
Within Whole genome sequencing (WGS) data, we explored the presence of rare coding damaging variants in voltage-gated calcium channels (VGCCs) genes, to investigate their role in ASD development in the affected individuals of our cohort
Summary
Autism Spectrum Disorder (ASD) is a group of clinically heterogeneous neurodevelopmental disorders with a prevalence of >1% [1], characterized by impairments in communication and social interaction, and the presence of repetitive and restrictive behaviors [2].ASD is a multifactorial disorder, with a strong genetic component and an estimated heritability of 60–90% [3, 4]. CACNA1H Variants in ASD Susceptibility interplay of rare deleterious variants and common low-risk alleles. The discovery of rare, highly penetrant, variants in a proportion of cases (10–25%) [5], contributed to the identification of numerous candidate genes, showing functional convergence on a small set of common pathological pathways. Calcium signaling has been consistently implicated in the molecular bases of ASD and associated comorbidities [6–8]. It represents a universal and versatile pathway involved in a wide range of cellular processes including synaptic plasticity, by modulating neurotransmitter release and shaping of the synaptic membrane composition [9]. Perturbation of intracellular calcium homeostasis caused by disruption of VGCCs genes has been associated to increased ASD susceptibility [8, 9, 12]
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