Human Gene Module / Chromosome 22 / PRODH

PRODHProline dehydrogenase (oxidase) 1

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 8
Rare Variants / Common Variants
17 / 0
Aliases
PRODH, HSPOX2,  PIG6,  POX1,  PRODH2,  TP53I6, PRODH
Associated Syndromes
-
Chromosome Band
22q11.21
Associated Disorders
EP, ASD, EPS
Relevance to Autism

Patients with hyperprolinemia type I caused by biallelic PRODH mutations have been shown to exhibit early onset and severe neurological features including autistic features (Afenjar et al., 2007).

Molecular Function

This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 [MIM:239500] and susceptibility to schizophrenia 4 (SCZD4) [MIM:600850]. This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PRODH (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Early neurological phenotype in 4 children with biallelic PRODH mutations Afenjar A , et al. (2007) No -
2 Support Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation Guilmatre A , et al. (2009) Yes -
3 Support Reduced transcript expression of genes affected by inherited and de novo CNVs in autism Nord AS , et al. (2011) Yes -
4 Positive Association Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes Radoeva PD , et al. (2014) No ASD
5 Negative Association The 22q11 PRODH/DGCR6 deletion is frequent in hyperprolinemic subjects but is not a strong risk factor for ASD Richard AC , et al. (2016) Yes -
6 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No Epilepsy/seizures, schizophrenia
7 Support - Hu C et al. (2023) Yes -
8 Support - Amerh S Alqahtani et al. (2023) No -
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 21448237 Nord AS , et al. (2011)
- - copy_number_loss Familial Maternal - 28708303 Chrot E , et al. (2017)
- - copy_number_loss Unknown - Simplex 19736351 Guilmatre A , et al. (2009)
- - copy_number_loss Familial Maternal Simplex 19736351 Guilmatre A , et al. (2009)
- - copy_number_loss Familial Paternal Simplex 19736351 Guilmatre A , et al. (2009)
- stop c55 stop_gained Familial Paternal Simplex 17412540 Afenjar A , et al. (2007)
- - copy_number_loss Unknown Not maternal Simplex 17412540 Afenjar A , et al. (2007)
- - copy_number_loss Familial Both parents Simplex 17412540 Afenjar A , et al. (2007)
c.1004A>G p.Asn335Ser missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.1772G>C p.Arg591Pro missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.1397C>T p.Thr466Met missense_variant Familial Paternal - 28708303 Chrot E , et al. (2017)
- p.Arg185Trp missense_variant Familial Maternal Simplex 17412540 Afenjar A , et al. (2007)
c.1322T>C p.Val441Ala missense_variant Familial Maternal Simplex 17412540 Afenjar A , et al. (2007)
c.1357C>T p.Arg453Cys missense_variant Familial Paternal Simplex 17412540 Afenjar A , et al. (2007)
c.1397C>T p.Thr466Met missense_variant Familial Maternal Simplex 17412540 Afenjar A , et al. (2007)
c.1397C>T p.Thr466Met missense_variant Familial Both parents Simplex 17412540 Afenjar A , et al. (2007)
c.1322T>C p.Leu441Pro missense_variant Familial Both parents Multiplex 37799141 Amerh S Alqahtani et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A recurrent 350 kb deletion spanning the PRODH gene was identified in 9 of 260 ASD cases and 1of 236 controls (P=0.02) (PMID 19736351). Patients with hyperprolinemia type I caused by biallelic PRODH mutations have been shown to exhibit early onset and severe neurological features including autistic features (Afenjar et al., 2007). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22.

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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."

10/1/2019
3S
icon
2S

Decreased from 3S to 2S

New Scoring Scheme
Description

A recurrent 350 kb deletion spanning the PRODH gene was identified in 9 of 260 ASD cases and 1of 236 controls (P=0.02) (PMID 19736351). Patients with hyperprolinemia type I caused by biallelic PRODH mutations have been shown to exhibit early onset and severe neurological features including autistic features (Afenjar et al., 2007). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22.

Reports Added
[New Scoring Scheme]
7/1/2017
3S
icon
3S

Decreased from 3S to 3S

Description

A recurrent 350 kb deletion spanning the PRODH gene was identified in 9 of 260 ASD cases and 1of 236 controls (P=0.02) (PMID 19736351). Patients with hyperprolinemia type I caused by biallelic PRODH mutations have been shown to exhibit early onset and severe neurological features including autistic features (Afenjar et al., 2007). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22.

Reports Added
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
1/1/2016
3S
icon
3S

Decreased from 3S to 3S

Description

A recurrent 350 kb deletion spanning the PRODH gene was identified in 9 of 260 ASD cases and 1of 236 controls (P=0.02) (PMID 19736351). Patients with hyperprolinemia type I caused by biallelic PRODH mutations have been shown to exhibit early onset and severe neurological features including autistic features (Afenjar et al., 2007). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22.

Reports Added
[Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.2009] [Reduced transcript expression of genes affected by inherited and de novo CNVs in autism.2011] [Early neurological phenotype in 4 children with biallelic PRODH mutations.2007] [Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.2014]
7/1/2015
icon
3S

Increased from to 3S

Description

A recurrent 350 kb deletion spanning the PRODH gene was identified in 9 of 260 ASD cases and 1of 236 controls (P=0.02) (PMID 19736351). Patients with hyperprolinemia type I caused by biallelic PRODH mutations have been shown to exhibit early onset and severe neurological features including autistic features (Afenjar et al., 2007). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22.

Krishnan Probability Score

Score 0.48097845684811

Ranking 7993/25841 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 4.7536314971685E-6

Ranking 14503/18225 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 0.94541586535821

Ranking 16461/18665 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 115/461 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 -0.034091864539361

Ranking 9832/20870 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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