Human Gene Module / Chromosome 3 / ALDH1L1

ALDH1L1aldehyde dehydrogenase 1 family member L1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 7
Rare Variants / Common Variants
11 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
3q21.3
Associated Disorders
-
Relevance to Autism

Rare de novo variants in the ALDH1L1 gene have been identified in ASD probands, including a de novo missense variant (p.Asn900His) in a proband from the Simons Simplex Collection (Iossifov et al., 2014; Yuen et al. 2017; Turner et al., 2017; Satterstrom et al., 2020), while a paternally-inherited loss-of-function variant in this gene was identified in an ASD proband from a multiplex family from the iHART cohort (Ruzzo et al. 2019). Functional assessment of the ASD-associated p.Asn900His missense variant in Drosophila using a rescue-based strategy in Macrogliese et al., 2022 demonstrated that humanized flies carrying the ALDH1L1-p.Asn900His mutation displayed a significant reduction in courtship and an increase in grooming behavior compared to the humanized reference fly or the TG4 mutant alone, potentially indicating that this variant acts as some sort of gain-of-function allele.

Molecular Function

The protein encoded by this gene catalyzes the conversion of 10-formyltetrahydrofolate, nicotinamide adenine dinucleotide phosphate (NADP+), and water to tetrahydrofolate, NADPH, and carbon dioxide. The encoded protein belongs to the aldehyde dehydrogenase family. Loss of function or expression of this gene is associated with decreased apoptosis, increased cell motility, and cancer progression.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ALDH1L1 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Recent Recommendation - Marcogliese PC et al. (2022) Yes -
7 Support - Wang J et al. (2023) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.7+1042C>G - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.889-185G>T - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.1374+221G>A - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1107-1516C>T - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1107-2296T>A - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.1502+46C>G - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1106+3997G>C - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.2348-4G>T - splice_region_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.701T>C p.Ile234Thr missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.2698A>C p.Asn900His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.51C>A p.Cys17Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

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.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49073798014557

Ranking 5993/25841 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 9.6178369541729E-6

Ranking 14237/18225 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 0.83293076384878

Ranking 2929/18665 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 0.005679886284141

Ranking 8516/20870 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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