Human Gene Module / Chromosome 6 / ALDH5A1

ALDH5A1aldehyde dehydrogenase 5 family, member A1 (succinate-semialdehyde dehydrogenase )

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
6 / 18
Rare Variants / Common Variants
15 / 0
EAGLE Score
2.35
Limited Learn More
Aliases
ALDH5A1, SSDH,  SSADH
Associated Syndromes
-
Chromosome Band
6p22.3
Associated Disorders
DD/NDD, ADHD, ID, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism.

Molecular Function

The encoded protein is a mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ALDH5A1 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Clinical spectrum of succinic semialdehyde dehydrogenase deficiency Pearl PL , et al. (2003) No Autism
2 Recent Recommendation Succinic semialdehyde dehydrogenase deficiency (SSADH) (4-hydroxybutyric aciduria, gamma-hydroxybutyric aciduria) Gordon N (2004) No -
3 Recent Recommendation Testicular germ cell tumors. Clinically relevant pathologic findings Ro JY , et al. (1991) No -
4 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
5 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
6 Support SSADH deficiency possibly associated with enzyme activity-reducing SNPs Akiyama T , et al. (2016) No DD, ASD, epilepsy
7 Support Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders Reuter MS , et al. (2017) No ID, hypotonia
8 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
9 Support Bi-allelic Mutations in ALDH5A1 is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability Fattahi M et al. (2020) No ASD, ADHD, DD, ID, epilepsy/seizures
10 Support - Cerminara M et al. (2021) Yes DD, ID
11 Support - Brea-Fernández AJ et al. (2022) No -
12 Support - Zhou X et al. (2022) Yes -
13 Support - Cirnigliaro M et al. (2023) Yes -
14 Support - Wardiya Afshar-Saber et al. (2024) No -
15 Support - Natalia Alexandra Julia-Palacios et al. (2024) No -
16 Support - Itay Tokatly Latzer et al. (2024) No -
17 Highly Cited Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues Stewart MJ , et al. (1996) No -
18 Support Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria) Chambliss KL , et al. (1998) No Autism
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.74G>A p.Arg25His missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1213-2A>C - splice_site_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.664G>A p.Gly222Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
G>A - splice_site_variant Familial Both parents Simplex 9683595 Chambliss KL , et al. (1998)
c.1145G>A p.Arg382His missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.638G>A p.Arg213Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.612G>A p.Trp204Ter stop_gained Familial Maternal Simplex 33679889 Cerminara M et al. (2021)
c.612G>A p.Trp204Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1586G>A p.Gly529Glu missense_variant Familial Paternal Simplex 27056292 Akiyama T , et al. (2016)
c.1402+1G>T - splice_site_variant Familial Both parents Multiplex 28097321 Reuter MS , et al. (2017)
c.538C>T p.His180Tyr missense_variant Familial Paternal Simplex 33679889 Cerminara M et al. (2021)
G>T - splice_site_variant Familial Both parents Extended multiplex 9683595 Chambliss KL , et al. (1998)
c.1321G>A p.Gly441Arg missense_variant Familial Both parents Multiplex 32621952 Fattahi M et al. (2020)
c.698C>T p.Thr233Met missense_variant Familial Both parents - 35322241 Brea-Fernández AJ et al. (2022)
c.858del p.Asp287IlefsTer27 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

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."

1/1/2021
1
icon
1

Score remained at 1

Description

Homozygous mutations in ALDH5A1 are responsible for succinic semialdehyde dehydrogenase (SSADH) deficiency (OMIM 271980), a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. Clinical evaluation of 51 patients with SSADH deficiency in Pearl et al., 2003 identified clinical findings including mild-moderate intellectual disability, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, and seizures. Cases with SSADH deficiency have also been identified that present with or were diagnosed with autism (Chambliss et al., 1998; Akiyama et al., 2016). Two de novo missense variants in ALDHA1 were identified in ASD probands in De Rubeis et al., 2014 and Iossifov et al., 2014, although one of these variants was predicted to be benign and was also present in dbSNP.

Reports Added
[Case Report: Whole Exome Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Autism Spectrum Disorder, Intellectual Disability, Hyperactivity, Sleep and Gastrointestinal Distur2021]
7/1/2020
1
icon
1

Score remained at 1

Description

Homozygous mutations in ALDH5A1 are responsible for succinic semialdehyde dehydrogenase (SSADH) deficiency (OMIM 271980), a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. Clinical evaluation of 51 patients with SSADH deficiency in Pearl et al., 2003 identified clinical findings including mild-moderate intellectual disability, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, and seizures. Cases with SSADH deficiency have also been identified that present with or were diagnosed with autism (Chambliss et al., 1998; Akiyama et al., 2016). Two de novo missense variants in ALDHA1 were identified in ASD probands in De Rubeis et al., 2014 and Iossifov et al., 2014, although one of these variants was predicted to be benign and was also present in dbSNP.

Reports Added
[Bi-allelic Mutations in ALDH5A1 is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability2020]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Homozygous mutations in ALDH5A1 are responsible for succinic semialdehyde dehydrogenase (SSADH) deficiency (OMIM 271980), a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. Clinical evaluation of 51 patients with SSADH deficiency in Pearl et al., 2003 identified clinical findings including mild-moderate intellectual disability, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, and seizures. Cases with SSADH deficiency have also been identified that present with or were diagnosed with autism (Chambliss et al., 1998; Akiyama et al., 2016). Two de novo missense variants in ALDHA1 were identified in ASD probands in De Rubeis et al., 2014 and Iossifov et al., 2014, although one of these variants was predicted to be benign and was also present in dbSNP.

Reports Added
[New Scoring Scheme]
1/1/2019
S
icon
S

Increased from S to S

Description

Homozygous mutations in ALDH5A1 are responsible for succinic semialdehyde dehydrogenase (SSADH) deficiency (OMIM 271980), a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. Clinical evaluation of 51 patients with SSADH deficiency in Pearl et al., 2003 identified clinical findings including mild-moderate intellectual disability, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, and seizures. Cases with SSADH deficiency have also been identified that present with or were diagnosed with autism (Chambliss et al., 1998; Akiyama et al., 2016). Two de novo missense variants in ALDHA1 were identified in ASD probands in De Rubeis et al., 2014 and Iossifov et al., 2014, although one of these variants was predicted to be benign and was also present in dbSNP.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
1/1/2017
S
icon
S

Increased from S to S

Description

Homozygous mutations in ALDH5A1 are responsible for succinic semialdehyde dehydrogenase (SSADH) deficiency (OMIM 271980), a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. Clinical evaluation of 51 patients with SSADH deficiency in Pearl et al., 2003 identified clinical findings including mild-moderate intellectual disability, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, and seizures. Cases with SSADH deficiency have also been identified that present with or were diagnosed with autism (Chambliss et al., 1998; Akiyama et al., 2016). Two de novo missense variants in ALDHA1 were identified in ASD probands in De Rubeis et al., 2014 and Iossifov et al., 2014, although one of these variants was predicted to be benign and was also present in dbSNP.

Reports Added
[Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.2017]
4/1/2016
S
icon
S

Increased from S to S

Description

Homozygous mutations in ALDH5A1 are responsible for succinic semialdehyde dehydrogenase (SSADH) deficiency (OMIM 271980), a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. Clinical evaluation of 51 patients with SSADH deficiency in Pearl et al., 2003 identified clinical findings including mild-moderate intellectual disability, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, and seizures. Cases with SSADH deficiency have also been identified that present with or were diagnosed with autism (Chambliss et al., 1998; Akiyama et al., 2016). Two de novo missense variants in ALDHA1 were identified in ASD probands in De Rubeis et al., 2014 and Iossifov et al., 2014, although one of these variants was predicted to be benign and was also present in dbSNP.

Reports Added
[Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria).1998] [Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.2003] [Testicular germ cell tumors. Clinically relevant pathologic findings.1991] [Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues.1996] [Succinic semialdehyde dehydrogenase deficiency (SSADH) (4-hydroxybutyric aciduria, gamma-hydroxybutyric aciduria).2004] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [SSADH deficiency possibly associated with enzyme activity-reducing SNPs.2016]
1/1/2016
S
icon
S

Increased from S to S

Description

No published test of autism association; Pearl et al. (2003) (PMID: 12743223) indicates a syndrome with autistic behaviors, language dysfunction

Reports Added
[Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria).1998] [Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.2003] [Testicular germ cell tumors. Clinically relevant pathologic findings.1991] [Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues.1996] [Succinic semialdehyde dehydrogenase deficiency (SSADH) (4-hydroxybutyric aciduria, gamma-hydroxybutyric aciduria).2004] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014]
Krishnan Probability Score

Score 0.46850659769475

Ranking 9013/25841 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 0.0029042616969501

Ranking 11014/18225 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 0.77094951756062

Ranking 1785/18665 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 0.17857754018066

Ranking 4633/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
C17ORF90 oxidoreductase-like domain containing 1 Human Protein Binding 339229 Q5BKU9
C1ORF85 GAN Human Protein Binding 112770 Q8WWB7
FGL1 Fibrinogen-like protein 1 Human Protein Binding 2267 Q08830
GATC Glutamyl-tRNA(Gln) amidotransferase subunit C, mitochondrial Human Protein Binding 283459 O43716
MAGEA11 melanoma antigen family A11 Human Protein Binding 4110 G5E962
MRPL50 mitochondrial ribosomal protein L50 Human Protein Binding 54534 Q8N5N7
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