Human Gene Module / Chromosome 15 / ALDH1A3

ALDH1A3aldehyde dehydrogenase 1 family member A3

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
1 / 7
Rare Variants / Common Variants
22 / 0
Aliases
ALDH1A3, ALDH1A6,  ALDH6,  RALDH3
Associated Syndromes
-
Chromosome Band
15q26.3
Associated Disorders
ID, ASD
Relevance to Autism

Homozygosity for one splice-site and two missense mutations in the ALDH1A3 gene was identified in three consanguineous families segregating with anophthalmia and microphthalmia (A/M); in one of these families, affected individuals with a homozygous missense variant in ALDH1A3 were also diagnosed with autism (Fares-Taie et al., 2013). However, in a report in which additional individuals with anophthalmia and microphthalmia (A/M) also presented with autistic features, the authors suggested that such features may be the result of social deprivation and inadequate parenting during early infancy, rather than ALDH1A3 mutations per se (Nur Semerci et al., 2014).

Molecular Function

This gene encodes an aldehyde dehydrogenase enzyme that uses retinal as a substrate. Mutations in this gene have been associated with microphthalmia, isolated 8.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to ALDH1A3 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary ALDH1A3 mutations cause recessive anophthalmia and microphthalmia Fares-Taie L , et al. (2013) No ASD
2 Support Mutations in ALDH1A3 cause microphthalmia Aldahmesh MA , et al. (2013) No ASD, ID
3 Recent Recommendation A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia Roos L , et al. (2013) No ASD, ID
4 Negative Association Novel splice-site and missense mutations in the ALDH1A3 gene underlying autosomal recessive anophthalmia/microphthalmia Semerci CN , et al. (2014) No Autistic features
5 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
6 Support - Zhou X et al. (2022) Yes -
7 Support - Kesim Y et al. (2023) No ASD or autistic features, DD, ID, epilepsy/seizure
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.724G>A p.Ala242Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.987G>A p.Glu329%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.100-2A>G - splice_site_variant Familial Paternal Simplex 36997679 Kesim Y et al. (2023)
c.566G>A p.Trp189Ter stop_gained Familial Maternal Simplex 36997679 Kesim Y et al. (2023)
c.1233+2T>C - splice_site_variant Familial Both parents Simplex 36997679 Kesim Y et al. (2023)
c.434C>T p.Ala145Val missense_variant Unknown - Multiplex 23646827 Aldahmesh MA , et al. (2013)
c.845G>C p.Gly282Ala missense_variant Familial Maternal Simplex 36997679 Kesim Y et al. (2023)
c.953C>A p.Ser318Tyr missense_variant Familial Paternal Simplex 36997679 Kesim Y et al. (2023)
c.1459A>G p.Arg487Gly missense_variant Familial Paternal Simplex 36997679 Kesim Y et al. (2023)
c.874G>T p.Asp292Tyr missense_variant Familial Maternal Multiplex 36997679 Kesim Y et al. (2023)
c.1393A>T p.Ile465Phe missense_variant Familial Paternal Multiplex 36997679 Kesim Y et al. (2023)
c.434C>T p.Ala145Val missense_variant Familial Both parents Simplex 36997679 Kesim Y et al. (2023)
c.847_849del p.Gly283del inframe_deletion Familial Maternal Simplex 36997679 Kesim Y et al. (2023)
c.475+1G>T - splice_site_variant Familial Both parents Simplex 23312594 Fares-Taie L , et al. (2013)
c.521G>A p.Cys174Tyr missense_variant Familial Both parents Multiplex 24024553 Roos L , et al. (2013)
c.1144G>A p.Gly382Arg missense_variant Familial Both parents Multiplex 36997679 Kesim Y et al. (2023)
c.1398C>A p.Asn466Lys missense_variant Familial Both parents Multiplex 24568872 Semerci CN , et al. (2014)
c.1477G>C p.Ala493Pro missense_variant Familial Both parents Simplex 23312594 Fares-Taie L , et al. (2013)
c.538-3C>T - splice_site_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1105A>T p.Ile369Phe missense_variant Familial Both parents Multiplex 23646827 Aldahmesh MA , et al. (2013)
c.666G>A p.Glu222= splice_site_variant Familial Both parents Extended multiplex 24568872 Semerci CN , et al. (2014)
c.265C>T p.Arg89Cys missense_variant Familial Both parents Extended multiplex 23312594 Fares-Taie L , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Homozygosity for one splice-site and two missense mutations in the ALDH1A3 gene was identified in three consanguineous families segregating with anophthalmia and microphthalmia (A/M); in one of these families, affected individuals with a homozygous missense variant in ALDH1A3 were also diagnosed with autism (Fares-Taie et al., 2013). Additional studies have identified homozygous missense variants in the ALDH1A3 gene in patients with anophthalmia and microphthalmia (A/M) and autism or autistic features (Aldahmesh et al., 2013; Roos et al., 2014). However, in a report in which additional individuals with anophthalmia and microphthalmia (A/M) also presented with autistic features, the authors suggested that such features may be the result of social deprivation and inadequate parenting during early infancy, rather than ALDH1A3 mutations per se (Nur Semerci et al., 2014).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Homozygosity for one splice-site and two missense mutations in the ALDH1A3 gene was identified in three consanguineous families segregating with anophthalmia and microphthalmia (A/M); in one of these families, affected individuals with a homozygous missense variant in ALDH1A3 were also diagnosed with autism (Fares-Taie et al., 2013). Additional studies have identified homozygous missense variants in the ALDH1A3 gene in patients with anophthalmia and microphthalmia (A/M) and autism or autistic features (Aldahmesh et al., 2013; Roos et al., 2014). However, in a report in which additional individuals with anophthalmia and microphthalmia (A/M) also presented with autistic features, the authors suggested that such features may be the result of social deprivation and inadequate parenting during early infancy, rather than ALDH1A3 mutations per se (Nur Semerci et al., 2014).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.44471775975726

Ranking 15783/25841 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 0.92410068514239

Ranking 2986/18225 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 0.93128966327936

Ranking 11659/18665 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
Larsen Cumulative Evidence Score

Score 22

Ranking 90/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.2465753045044

Ranking 3522/20870 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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