CTNNA3

• Haploinsufficiency score: 0
• Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: Complex Neurodevelopmental Disorder

Evidence for haploinsufficiency phenotype

PubMed ID	Description
23375656	Girirajan S et al., 2013. They designed a microarray, and performed on 2,588 autistic individuals from simplex and multiplex families and in 580 controls. They identified several recurrent large hotspot events, and also smaller atypical CNVs. CTNAA3 is not within the hotspots, but in the genomic backbone, which is also covered by their microarray. They performed targeted discovery of CNVs affecting known autism candidate genes (n=430 genes), including genes reported in recent studies as well as those curated in autism databases. There were 60 candidate genes enriched for exon-disrupting CNVs in ASD cases versus controls, and CTNNA3 was one of them. There were 22 ASD patients with CNVs in CTNNA3, 21 were deletions (1 de novo, 20 inherited), and 1 was duplication. However, they didn?t mention if these CNVs in CTNNA3 were the only genetic change in those individuals.
21658582	Levy D et al., 2011. They did genome wide CGH on ASD patients, and data raise the suspicion for USP7, CTNNA3, and genes encoding several related voltage-gated calcium channels. Deletions of CTNNA3 were detected in four different ASD patients, and one patient with ID, ASD, and EP. All of these 4 deletions were inherited.
20427753	PMID: 20427753 Sundaram SK et. al., 2010. A deletion containing CTNNA3 was recurrent in two Tourette syndrome (TS) patients. Tourette syndrome is a neurobehavioral disorder manifest particularly by motor and vocal tics and associated with behavioral abnormalities (OMIM 137580). Both of the deletions were inherited. PMID: 19546859 Elia J et al., 2010. Identified 222 inherited CNVs within 335 Attention-deficit/hyperactivity disorder (ADHD) patients. CTNNA3 was one of the genes significantly enriched in ADHD CNV deletions using Gene Ontology (GO) analysis. Intronic deletions: PMID: 22738016 Lesca G et. al., 2012 did aCGH in 61 patients with slow?wave sleep syndrome (CSWSS) and the Landau?Kleffner (LKS) syndrome which are two rare epileptic encephalopathies. In one of the patients, a de novo intronic deletion was detected in CTNNA3 gene. Another patient had an inherited partial deletion of CTNNA3. A third patient had an inherited intronic deletion in CTNNA3 gene which was previously reported. PMID: 20531469 Pinto D et al., 2010. They analyzed the genome-wide characteristics of rare (<1% frequency) copy number variation using dense genotyping arrays, on 996 ASD individuals of European ancestry to 1,287 matched controls. Among the 9 deletions in CTNNA3 detected in 9 different patients, 6 were intronic deletions, 3 were exonic ones. However, 2 out of the 3 exonic deletions were absent in affected sibling of the patients.

Haploinsufficiency phenotype comments:

Given the number of inherited variants observed within this gene and the pLI score of 0, we are opting to score this gene at 0 at this time. Additional evidence is needed to determine the role this gene plays in complex neurodevelopmental disorder. Of note: arrhythmogenic right ventricular dysplasia, familial 13 (ARVD13): PMID: 23136403 In 76 Italian probands with ARVD who were negative for mutation in 5 known ARVD-associated genes, van Hengel et al. (2013) analyzed the candidate gene CTNNA3 and identified different heterozygous mutations in 2 of the probands, a missense mutation (V94D; OMIM 607667.0001) and an in-frame 3-bp deletion (OMIM 607667.0002). Neither mutation was found in 250 ethnically matched controls or in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases.

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

Evidence for gain of function phenotype

PubMed ID	Description
23632794	Nava C et al., 2014. They screened 194 individuals with ASDs for CNVs using Illumina SNP arrays, and detected a deletion and a duplication of CTNNA3 in one patient each. They did not mention whether this deletion and duplication was de novo or inherited. They only stated that they also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents.
23375656	Girirajan S et al., 2013. They designed a microarray, and performed on 2,588 autistic individuals from simplex and multiplex families and in 580 controls. They identified several recurrent large hotspot events, and also smaller atypical CNVs. CTNAA3 is not within the hotspots, but in the genomic backbone, which is also covered by their microarray. They performed targeted discovery of CNVs affecting known autism candidate genes (n=430 genes), including genes reported in recent studies as well as those curated in autism databases. There were 60 candidate genes enriched for exon-disrupting CNVs in ASD cases versus controls, and CTNNA3 was one of them. There were 22 ASD patients with CNVs in CTNNA3, 21 were deletions (1 de novo, 20 inherited), and 1 was duplication (inherited). However, they didn?t mention if these CNVs in CTNNA3 were the only genetic change in those individuals.