Human Gene Module / Chromosome 9 / ABCA2

ABCA2ATP binding cassette subfamily A member 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
16 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
9q34.3
Associated Disorders
-
Relevance to Autism

"A total of seven de novo missense variants in the ABCA2 gene have been identified in ASD probands from the Simons Simplex Collection, the MSSNG cohort, the SPARK cohort, and a Qatari ASD cohort (Iossifov et al., 2014; Yuen et al., 2017; Zhou et al., 2022; Al-Sarraj et al., 2024). ABCA2 had previously been prioritized as a schizophrenia susceptibility gene in Wang et al., 2015 based on harboring a de novo damaging variant that was identified in a Chinese schizophrenia patient, being enriched for ""brain-critical exons"", being highly interconnected with other genes in a co-expression network of specific anatomical subregions of the prenatal frontal cortex and temporal-parietal regions, and being a highly constrained gene in which de novo variants would be unlikely to occur by chance in schizophrenia patients."

Molecular Function

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is highly expressed in brain tissue and may play a role in macrophage lipid metabolism and neural development. Homozygous variants in this gene are responsible for intellectual developmental disorder with poor growth and with or without seizures or ataxia (IDPOGSA; OMIM 618808), an autosomal recessive neurologic disorder characterized by global developmental delay apparent from infancy, hypotonia, and poor overall growth, sometimes with borderline microcephaly.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ABCA2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support - Qiang Wang et al. (2015) No -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Primary - Yasser Al-Sarraj et al. (2024) Yes -
7 Support - Suhua Chang et al. () Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3362G>A p.Arg1121Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4051A>C p.Lys1351Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6064G>A p.Gly2022Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7353C>T p.Phe2451= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.4814C>T p.Pro1605Leu missense_variant De novo - - 26666178 Qiang Wang et al. (2015)
c.371C>G p.Thr124Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.753C>T p.Pro251= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.6723C>T p.Asp2241= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3174G>A p.Thr1058= synonymous_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.6723C>T p.Asp2241= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.5187+7G>A - splice_region_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.5533G>A p.Val1845Met missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4051A>C p.Lys1351Gln missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.2253C>T p.Ala751= synonymous_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.4857C>T p.Phe1619= synonymous_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1190A>G p.Asp397Gly missense_variant De novo - Unknown 38572415 Yasser Al-Sarraj et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

7/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.52882930018158

Ranking 1573/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99999951572874

Ranking 265/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93943462706058

Ranking 14209/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.03723719252787

Ranking 9949/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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