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Relevance to Autism

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015).

Molecular Function

This gene encodes the pore-forming alpha-1A subunit, which is predominantly expressed in neuronal tissue, for voltage-dependent calcium channels. Mutations in this gene are associated with several neurological disorders: episodic ataxia, type 2 (OMIM 108500); migraine, familial hemiplegic, 1 (OMIM 141500); and spinocerebellar atxia 6 (OMIM 183086).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.
DD, ID, ADHD, ASD, epileptic encephalopathy
Learning difficulties, ataxia
Negative Association
Genetic Evidence for Possible Involvement of the Calcium Channel Gene CACNA1A in Autism Pathogenesis in Chinese Han Population.
ASD
Support
Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant.
Epilepsy/seizures
ID, ataxia
Support
The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing
ASD
Support
CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures.
Support
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
Epilepsy/seizures
DD/ID
Support
The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing
ID
Support
A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.
Cerebellar ataxia
Oculomotor apraxia
Support
The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.
ASD, epilepsy/seizures
Support
Lessons learned from additional research analyses of unsolved clinical exome cases.
DD
Hypotonia, cerebellar atrophy
Support
Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...
DD
Support
Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations
ID
DD, stereotypy
Support
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
ID
Support
Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.
ASD
Epilepsy/seizures
Support
Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort
Epilepsy/seizures
ASD
Support
De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies.
Epilepsy/seizures
Support
The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.
Epilepsy/seizures
ID
Support
Genome sequencing broadens the range of contributing variants with clinical implications in schizophrenia
SCZ
ID
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Recent Recommendation
De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.
Recent Recommendation
Isolated P/Q Calcium Channel Deletion in Layer VI Corticothalamic Neurons Generates Absence Epilepsy.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN707R001 
 stop_gained 
 c.3832C>T 
 p.Arg1278Ter 
 Familial 
 Paternal 
 Multi-generational 
 GEN707R002 
 frameshift_variant 
 c.2867_2869del 
 p.Asp956del 
 Familial 
 Maternal and paternal 
 Multi-generational 
 GEN707R003 
 splice_site_variant 
 c.873G>A 
 p.Trp291Ter 
 Familial 
 Maternal 
 Multi-generational 
 GEN707R004 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multi-generational 
 GEN707R005 
 synonymous_variant 
 c.1173G>C 
 p.Gly391= 
 De novo 
 NA 
 Simplex 
 GEN707R006 
 missense_variant 
 c.301G>C 
 p.Glu101Gln 
 De novo 
 NA 
  
 GEN707R007 
 missense_variant 
 c.653C>T 
 p.Ser218Leu 
 Unknown 
  
  
 GEN707R008 
 missense_variant 
 c.2137G>A 
 p.Ala713Thr 
 De novo 
 NA 
  
 GEN707R009 
 missense_variant 
 c.2137G>A 
 p.Ala713Thr 
 Familial 
 Maternal 
 Multiplex 
 GEN707R010 
 missense_variant 
 c.4531G>T 
 p.Ala1511Ser 
 De novo 
 NA 
  
 GEN707R011 
 frameshift_variant 
 c.2040_2041del 
 p.Gln681GlyfsTer103 
 De novo 
 NA 
  
 GEN707R012 
 missense_variant 
 c.5015G>C 
 p.Arg1672Pro 
 De novo 
 NA 
 Simplex 
 GEN707R013 
 missense_variant 
 c.4106T>G 
 p.Val1369Gly 
 De novo 
 NA 
  
 GEN707R014 
 missense_variant 
 c.4174G>A 
 p.Val1392Met 
 De novo 
 NA 
 Simplex 
 GEN707R015 
 missense_variant 
 c.2134G>A 
 p.Ala712Thr 
 De novo 
 NA 
 Simplex 
 GEN707R016 
 missense_variant 
 c.835C>T 
 p.Arg279Cys 
 Familial 
  
 Multi-generational 
 GEN707R017 
 missense_variant 
 NM_023035.3:c.7178G>A 
 p.Gly2393Glu 
 Familial 
 Maternal 
  
 GEN707R018 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN707R019 
 missense_variant 
 c.5263G>A 
 p.Glu1755Lys 
 De novo 
 NA 
  
 GEN707R020 
 missense_variant 
 c.4046G>A 
 p.Arg1349Gln 
 De novo 
 NA 
  
 GEN707R021 
 inframe_deletion 
 c.4082_4084del 
 p.Lys1361del 
 De novo 
 NA 
  
 GEN707R022 
 missense_variant 
 c.4991G>A 
 p.Arg1664Gln 
 De novo 
 NA 
  
 GEN707R023 
 missense_variant 
 c.118G>T 
 p.Gly40Trp 
 De novo 
 NA 
  
 GEN707R024 
 missense_variant 
 ENSG00000141837:ENST00000573710:exon19:c.A2504C:p.N835T,ENSG00000141837:ENST00000360228:exon19:c.A25 
  
 De novo 
 NA 
  
 GEN707R025 
 frameshift_variant 
 c.2042_2043del 
 p.Gln681ArgfsTer103 
 Unknown 
  
 Simplex 
 GEN707R026 
 missense_variant 
 c.7205C>A 
 p.Pro2402Gln 
 De novo 
 NA 
 Simplex 
 GEN707R027 
 missense_variant 
 c.4055G>A 
 p.Arg1352Gln 
 De novo 
 NA 
  

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN707C001 
 intron_variant 
 rs12609735 
 c.294-22490A>G 
  
 553 Chinese Han ASD trios 
 Discovery 
 GEN707C002 
 intron_variant 
 rs7249246 
 c.293+17663A>C 
  
 553 Chinese Han ASD trios 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Deletion
 4
 
19
Deletion
 2
 
19
Deletion
 1
 
19
Deletion-Duplication
 28
 
19
Deletion-Duplication
 5
 
19
Deletion-Duplication
 3
 
19
Duplication
 1
 
19
Duplication
 1
 

No Animal Model Data Available

 

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