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Table 1 Key information of included studies

From: Genetic associations between voltage-gated calcium channels and autism spectrum disorder: a systematic review

ReferenceCountrySampleGeneMutationGain/loss of functionMethodMain Findings
Damaj et al. [10]Canada16 individuals with ASD-like behavioral deficitsCACNA1A(1)deletion
(2) point mutation
loss-of-functionwhole genome sequencingResults 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]AustriatsA-201 cellsCACNA1Dde novo variantgain-of-functionwhole-cell patch-clampThe 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]USA461ASD
480controls
CACNA1Hrare missense variantlose of function(1) Genotypic Analyses (2) DNA Sequence AnalysesThe study identified missense mutations in CACNA1H in 6 of 461 individuals with ASD.
Splawski et al .[42]USA13 TS
13 controls
CACNA1Cde novo missense variantgain-of-function(1) Genotypic Analyses (2) DNA SequencingThe result showed that the CACNA1C gain-of-function mutation causes the diverse physiological and developmental defects in TS.
Li et al .[23]China553 triosCACNA1ASNPs (1) SNP selection
(2) SNP genotyping
The study identified association of rs7249246 and rs12609735 with ASD.
Strom et al .[45]USA284 triosCACNA1GSNPs (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
CACNA2D4CNVs Microarray analysesThe 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
CACNA1Dde novo missense variantgain-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
CACNB2rare missense variantgain-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]China553 triosCACNA1CSNPs (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]USA2781 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]USA343 families with ASDCACNA2D3de novo variant DNA SequencingThe 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
CACNA1CSNPs genome-wide SNP genotypingThe 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)CACNB2SNPs genome-wide SNP genotypingThe result showed that SNPs within CACNA1C and CACNB2 were associated with ASD.
Hemara-Wahanui et al .[18]New Zealand27 families with ASDCACNA1Fnucleotide substitutiongain-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
CACNA1Frare missense variant DNA SequencingThe 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]USAskin fibroblast culturesIP3-mediated Ca 2+ release  High-throughput Ca2+ imagingThe study found a significantly reduction in IP3-mediated Ca2+ release from the ER.
Wen et al .[48]USAASD 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
CACNA1ASNPs Gene set enrichment analysisThe result showed that SNPs in CACNA1A to be among the top 15 SNPs contributing to the ASD diagnosis
Schmunk et al .[38]USAskin fibroblast culturesIP3-mediated Ca 2+ release  High-throughput Ca2+ imagingThe study found a significantly depressed IP3-mediated Ca2+ signals in ASD.
O'Roak et al .[31]USA209 trios(1)CACNA1D
(2)CACNA1E
CNVs Exome read-depth CNV analysisThe 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 variantloss of functionExome sequencingThe 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
CACNA2D3CNVs Microarray analysesThe study reported an enrichment of CACNA2D3 deletion in ASD subjects compared to controls
Jiang et al. [22]USA32 families with ASDCACNA1Crare missense variant Whole-genome sequencinIt found a rare missense mutation in CACNA1C (R1522Q) in a proband with ASD and an unaffected sibling.
Yuen et al. [51]Canada85 quartet families
(parents and two ASD-affected siblings)
CACNB2rare missense variant Whole-genome sequencingIt found a CACNB2 (V2D) mutation in two affected siblings.
Yatsenko et al .[50]USA20 ASDCACNA1Bduplication (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
CACNA2D4CNVs CGH microarrayThe study identified multiple novel CNVs in ASD subjects, including the loss of CACNA2D4.