Table 1 Key information of included studies

Damaj et al. [10]

Canada

16 individuals with ASD-like behavioral deficits

CACNA1A

(1)deletion

(2) point mutation

loss-of-function

whole genome sequencing

Results from sequencing revealed one CACNA1A gene deletion as well as two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant, which pointed to an association between CACNA1A variants and ASD symptoms.

Pinggera et al .[33]

Austria

tsA-201 cells

CACNA1D

de novo variant

gain-of-function

whole-cell patch-clamp

The study identified two de novo mutation, p.A749G and p.G407R, in ASD subjects, both demonstrated a

pronounced gain-of-function.

Splawski et al .[43]

USA

461ASD

480controls

CACNA1H

rare missense variant

lose of function

(1) Genotypic Analyses (2) DNA Sequence Analyses

The study identified missense mutations in CACNA1H in 6 of 461 individuals with ASD.

Splawski et al .[42]

USA

13 TS

13 controls

CACNA1C

de novo missense variant

gain-of-function

(1) Genotypic Analyses (2) DNA Sequencing

The result showed that the CACNA1C gain-of-function mutation causes the diverse physiological and developmental defects in TS.

Li et al .[23]

China

553 trios

CACNA1A

SNPs

(1) SNP selection

(2) SNP genotyping

The study identified association of rs7249246 and rs12609735 with ASD.

Strom et al .[45]

USA

284 trios

CACNA1G

SNPs

(1) SNP selection

(2) SNP genotyping

Markers within an interval containing the gene, CACNA1G, were found to be associated with ASD at a locally significant level.

Smith et al .[41]

USA

(1)69 ASD (2)35 parents

(3)89 CEU HapMap controls

CACNA2D4

CNVs

Microarray analyses

The study identified a rare homozygous deletion in a male proband that removed one copy of the CACNA2D4 calcium channel genes(12p13.33)

Pinggera et al .[34]

Germany

(1)1ASD

(2)tsA-201 cells

CACNA1D

de novo missense variant

gain-of-function

(1) DNA Sequencing

(2)whole-cell patch-clamp

The study identified a de novo missense mutation in CACNA1D (V401L) in a patient with ASD.

Breitenkamp et al .[5]

Germany

(1)155 ASD

(2)259 controls

CACNB2

rare missense variant

gain-of-function

(1) Genotypic Analyses

(2) DNA Sequencing

The study identified three missense mutations in CACNB2 gene in ASD subjects that result in a decelerated inactivation of the Cav1.2 subunit

Li et al .[23]

China

553 trios

CACNA1C

SNPs

(1) SNP selection

(2) SNP genotyping

The result found a nominal significant association between two SNPs (rs1006737 and rs4765905) in CACNA1C and ASD.

Lu et al .[25]

USA

2781 trios

(1)CACNA1C

(2)CACNA1G

(3)CACNA1I

SNPs

(1) SNP selection

(2) SNP genotyping

Four SNPs in three CCGs were associated with ASD. One, rs10848653, is located in CACNA1C.Two others, rs198538 and rs198545, located in CACN1G, and a fourth, rs5750860, located in CACNA1I.

Iossifov et al .[21]

USA

343 families with ASD

CACNA2D3

de novo variant

DNA Sequencing

The result identified a variation in CACNA2D3 that disrupted a splice junction associated with ASD (A/G).

Wang et al .[47]

USA

(1)780 families with ASD

(2)1204 affected subjects

(3)6491 control subjects

CACNA1C

SNPs

genome-wide SNP genotyping

The result found an relationship between SNPs in CACNA1C and ASD

Cross-Disorder Group [9]

USA

(1)33,332ASD

(2)27,888 controls

(1)CACNA1C (2)CACNB2

SNPs

genome-wide SNP genotyping

The result showed that SNPs within CACNA1C and CACNB2 were associated with ASD.

Hemara-Wahanui et al .[18]

New Zealand

27 families with ASD

CACNA1F

nucleotide substitution

gain-of-function

(1) DNA Sequencing

(2) Functional Analyses

The molecular genetic analyses revealed an I745T CACNA1F allele in a New Zealand family, some male probands also affected with ASD.

Myers et al .[27]

USA

(1)142 ASD

(2)143 SCZ

(3) 240controls

CACNA1F

rare missense variant

DNA Sequencing

The study found a rare causal CACNA1F variants associated with ASD.

Palmieri et al .[32]

USA

(1)6ASD

(2)6controls

Ca²⁺ concentration

Fluorimetric measure of Ca²⁺

The study found a significantly higher level of Ca²⁺ in ASD patients as compared to healthy controls.

Schmunk et al .[39]

USA

skin fibroblast cultures

IP3-mediated Ca ²⁺ release

High-throughput Ca²⁺ imaging

The study found a significantly reduction in IP3-mediated Ca2+ release from the ER.

Wen et al .[48]

USA

ASD genes

(1) Gene set enrichment analysis

(2)Pathway-pathway interactions

The results showed that the process “calcium-PRC (protein kinase C)-Ras-Raf-MAPK/ERK” was a major contributor to ASD pathophysiology.

Skafidas et al .[40]

Australia

(1) Index sample:2609 ASD

(2) Vlidation sample:737 ASD

CACNA1A

SNPs

Gene set enrichment analysis

The result showed that SNPs in CACNA1A to be among the top 15 SNPs contributing to the ASD diagnosis

Schmunk et al .[38]

USA

skin fibroblast cultures

IP3-mediated Ca ²⁺ release

High-throughput Ca²⁺ imaging

The study found a significantly depressed IP3-mediated Ca2+ signals in ASD.

O'Roak et al .[31]

USA

209 trios

(1)CACNA1D

(2)CACNA1E

CNVs

Exome read-depth CNV analysis

The result showed that rare de novo alleles of CACNA1D and CACNA1E contributed to the genetic etiology of ASD.

De Rubeis et al .[11]

USA

(1) 3871 ASD

(2)9937 controls

(1)CACNA2D3

(2) CACNA1D

de novo variant

loss of function

Exome sequencing

The result identified two de novo CACNA2D3 loss of function mutations in ASD cases and none in controls.

Girirajan et al .[17]

USA

(1) 2588 ASD

(2) 580 controls

CACNA2D3

CNVs

Microarray analyses

The study reported an enrichment of CACNA2D3 deletion in ASD subjects compared to controls

Jiang et al. [22]

USA

32 families with ASD

CACNA1C

rare missense variant

Whole-genome sequencin

It found a rare missense mutation in CACNA1C (R1522Q) in a proband with ASD and an unaffected sibling.

Yuen et al. [51]

Canada

85 quartet families

(parents and two ASD-affected siblings)

CACNB2

rare missense variant

Whole-genome sequencing

It found a CACNB2 (V2D) mutation in two affected siblings.

Yatsenko et al .[50]

USA

20 ASD

CACNA1B

duplication

(1) whole genome sequencing

(2) custom 9q34 microarray

The study found a duplication of the chromosomal region 9q43.3, comprising the gene CACNA1B, in 12 out of 20 patients.

Prasad et al .[36]

USA

(1)696 unrelated ASD

(2)1000 controls

CACNA2D4

CNVs

CGH microarray

The study identified multiple novel CNVs in ASD subjects, including the loss of CACNA2D4.