Human Gene Module / Chromosome 12 / PAH

PAHPhenylalanine hydroxylase

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
7 / 12
Rare Variants / Common Variants
22 / 0
Aliases
PAH, PH,  PKU,  PKU1
Associated Syndromes
-
Chromosome Band
12q23.2
Associated Disorders
ID, ASD
Relevance to Autism

Homozygous variants in the PAH gene were identified that segregated with ASD in two separate pedigrees (one multiplex, one simplex) consisting of affected children born to consanguineous parents (Yu et al., 2013).

Molecular Function

The PAH gene encodes the enzyme phenylalanine hydroxylase, which is the rate-limiting step in phenylalanine catabolism. Defects in PAH are the cause of phenylketonuria (PKU), non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA), and hyperphenylalaninemia (HPA) [MIM:261600].

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PAH (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Using whole-exome sequencing to identify inherited causes of autism Yu TW , et al. (2013) Yes -
2 Support Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders Reuter MS , et al. (2017) No ID
3 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders Jiao Q , et al. (2019) No -
4 Support Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders Gao C , et al. (2019) No Autistic features
5 Support Recessive gene disruptions in autism spectrum disorder Doan RN , et al. (2019) Yes -
6 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
7 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Macrocephaly
8 Support - Brea-Fernández AJ et al. (2022) No -
9 Support - N.Y.) (07/2) No -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Cirnigliaro M et al. (2023) Yes -
12 Support - Omri Bar et al. (2024) Yes OCD, ID
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.465T>G p.Arg155%3D synonymous_variant De novo - - 35901164 N.Y.) (07/2)
c.468A>G p.Ala156%3D synonymous_variant De novo - - 35901164 N.Y.) (07/2)
c.474G>A p.Arg158%3D synonymous_variant De novo - - 35901164 N.Y.) (07/2)
c.159G>A p.Arg53His missense_variant Familial - - 30945278 Jiao Q , et al. (2019)
c.567C>T p.Thr189Ile missense_variant Familial - - 30945278 Jiao Q , et al. (2019)
c.441+1G>A - splice_site_variant Familial Paternal Simplex 31674007 Wu H , et al. (2019)
c.729G>A p.Arg243Gln missense_variant Familial Paternal - 31178897 Gao C , et al. (2019)
c.876C>T p.Pro292Leu missense_variant Familial Maternal - 31178897 Gao C , et al. (2019)
c.783G>A p.Arg261Gln missense_variant Unknown - Unknown 31209396 Doan RN , et al. (2019)
c.843C>T p.Pro281Leu missense_variant Unknown - Unknown 31209396 Doan RN , et al. (2019)
c.688G>A p.Val230Ile missense_variant Unknown - Simplex 38256266 Omri Bar et al. (2024)
c.1314C>T p.Asn438%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1208C>T p.Ala403Val missense_variant Unknown - Simplex 38256266 Omri Bar et al. (2024)
c.782C>T p.Arg261Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.815G>T p.Gly272Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.704C>T p.Gln235Ter stop_gained Familial Both parents Multiplex 23352163 Yu TW , et al. (2013)
c.1315+1G>A - splice_site_variant Familial Maternal - 35322241 Brea-Fernández AJ et al. (2022)
c.561G>A p.Trp187Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.194T>C p.Ile65Thr missense_variant Familial Paternal - 35322241 Brea-Fernández AJ et al. (2022)
c.930C>T p.Ser310Phe missense_variant Familial Both parents Simplex 28097321 Reuter MS , et al. (2017)
c.593_614del p.Tyr198SerfsTer136 inframe_deletion Familial Both parents Simplex 23352163 Yu TW , et al. (2013)
c.1055del p.Gly352ValfsTer48 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

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.

4/1/2022
2
icon
1

Decreased from 2 to 1

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Homozygous variants in the PAH gene were found to segregate with ASD in two consanguineous families in Yu et al., 2013: a nonsense variant that segregated with ASD in a multiplex family, and an in-frame deletion of 7 amino acids that segregated with ASD in a simplex family. Defects in PAH are the cause of phenylketonuria (PKU), non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA), and hyperphenylalaninemia (HPA) [MIM:261600].

Reports Added
[Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Homozygous variants in the PAH gene were found to segregate with ASD in two consanguineous families in Yu et al., 2013: a nonsense variant that segregated with ASD in a multiplex family, and an in-frame deletion of 7 amino acids that segregated with ASD in a simplex family. Defects in PAH are the cause of phenylketonuria (PKU), non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA), and hyperphenylalaninemia (HPA) [MIM:261600].

Reports Added
[Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders.2019] [Recessive gene disruptions in autism spectrum disorder.2019] [Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

Homozygous variants in the PAH gene were found to segregate with ASD in two consanguineous families in Yu et al., 2013: a nonsense variant that segregated with ASD in a multiplex family, and an in-frame deletion of 7 amino acids that segregated with ASD in a simplex family. Defects in PAH are the cause of phenylketonuria (PKU), non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA), and hyperphenylalaninemia (HPA) [MIM:261600].

Reports Added
[The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019]
1/1/2017
3
icon
3

Decreased from 3 to 3

Description

Homozygous variants in the PAH gene were found to segregate with ASD in two consanguineous families in Yu et al., 2013: a nonsense variant that segregated with ASD in a multiplex family, and an in-frame deletion of 7 amino acids that segregated with ASD in a simplex family. Defects in PAH are the cause of phenylketonuria (PKU), non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA), and hyperphenylalaninemia (HPA) [MIM:261600].

Reports Added
[Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.2017]
4/1/2016
icon
3

Increased from to 3

Description

Homozygous variants in the PAH gene were found to segregate with ASD in two consanguineous families in Yu et al., 2013: a nonsense variant that segregated with ASD in a multiplex family, and an in-frame deletion of 7 amino acids that segregated with ASD in a simplex family. Defects in PAH are the cause of phenylketonuria (PKU), non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA), and hyperphenylalaninemia (HPA) [MIM:261600].

Krishnan Probability Score

Score 0.49406809867308

Ranking 3842/25841 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 1.1951974462996E-10

Ranking 16913/18225 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 0.68612488005344

Ranking 1074/18665 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 18

Ranking 113/461 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 -0.46268604039162

Ranking 18929/20870 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
PAH phenylalanine hydroxylase Human Protein Binding 5053 P00439
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