ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
19586927 Labrum et al. 2009 reported a total of 9 exonic deletions and 1 single exon duplication in CACNA1A with either episodic ataxia 2 (EA2) or familial hemiplegic migraine (FHM) (including those cases reported in the addendum). Deletions were detected using MLPA, and the authors report that "the presence of single nucleotide polymorphisms (SNPs) under the probe binding site was excluded by direct DNA sequencing." The authors also noted that "none of the deletions or the single duplication were detected in a panel of 180 normal control chromosomes" and that "the frequency of rearrangement mutations in [their] patient cohort [was] significantly different when compared to a control population (p,0.001; Fisher?s exact test)." At least 4 of these cases were shown to involve deletions of multiple consecutive exons. Family information was available for some of the cases, including a deletion of exon 6 that segregated with disease in 8 affected individuals in a 4-generation family.
21927611 Wan et al. 2011 described 3 additional probands with clinical diagnoses of episodic ataxia 2 and deletions of multiple exons in CACNA1A identified by MLPA, with breakpoints defined by long-range PCR. One of these deletions was de novo, and one was inherited from an affected parent; parents were unavailable for testing in the case of the third deletion.
25735478 Damaj et al. 2015 described 16 individuals from 4 non-consanguinous French-Canadian families with loss-of-function-type variants in CACNA1A: 1 intragenic deletion (85 kb, including exons 2-3 of 47 total; NM_001127221.1), 1 nonsense, 1 frameshift, and 1 splice-site. These mutations are predicted to result in a loss-of-function, however functional studies were not performed to prove a resultant haploinsufficiency. Each of these variants was inherited within their respective families; the most extensively studied family, Family 1 (the nonsense variant) had 4 documented segregations among affected individuals. Though many affected individuals within the families displayed features consistent with episodic ataxia 2, the authors also reported the presence of a "spectrum of cognitive impairment, including intellectual deficiency, executive dysfunction, ADHD and/or autism" amongst some of the affected individuals. For these families, the cognitive issues were the issues that initially brought them to medical attention, with the cerebellar symptoms being ascertained on detailed interview/examination.

Haploinsufficiency phenotype comments:

CACNA1A encodes the transmembrane subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel protein. Mutations in CACNA1A have been associated with a variety of overlapping autosomal dominant nervous system phenotypes, including spinocerebellar ataxia 6 (SCA6), episodic ataxia 2 (EA2), and familial hemiplegic migraine (FHM1). Intragenic/exonic CACNA1A loss-of-function-type copy number variants (deletions and duplications) have been identified in numerous individuals and families in association with EA2 and FHM1. SCA6 is caused by CAG repeat expansion. Due to the identification of numerous loss-of-function type alterations in CACNA1A, a 3 score for haploinsufficiency is assigned based on standard scoring criteria. NOTE: As yet, focal whole gene deletion of CACNA1A has not been reported in association with these phenotypes, although Auvin et al., 2009 (PMID 19874387) reported a non-focal 0.7 Mb deletion of 32 genes including CACNA1A in association with ID, epilepsy and infantile spasms. Functional studies to support a null effect of intragenic CACNA1A CNVs would be helpful.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity