Human Gene Module / Chromosome 8 / PUF60

PUF60poly(U) binding splicing factor 60

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
10 / 0
Aliases
-
Associated Syndromes
Verheij syndrome, DD, Verheij syndrome, DD, ID
Chromosome Band
8q24.3
Associated Disorders
-
Relevance to Autism

Trio whole-exome sequencing of 173 children diagnosed with developmental delay/intellectual disability from China in Li et al., 2024 identified a de novo nonsense variant in the PUF60 gene in a a male patient presenting with autism spectrum disorder, speech delay, short stature, and spine malformation. Additional de novo variants in the PUF60 gene, including a de novo loss-of-function variant and two de novo missense variants (one of which was predicted to be deleterious by CADD, REVEL, and MPC), were previously reported in ASD probands from the Autism Sequencing Consortium and the SPARK cohort (De Rubeis et al., 2014; Zhou et al., 2022). Heterozygous variants or contiguous gene deletions affecting PUF60 are also responsible for Verheij syndrome (OMIM 615583), a disorder characterized by characterized by growth retardation, delayed psychomotor development, dysmorphic facial features, and skeletal (mainly vertebral) abnormalities; 2/5 individuals with PUF60 variants described in El Chehadeh et al., 2016 were reported to have autism spectrum disorder, while 1/12 individuals with PUF60 variants described in Low et al., 2017 was reported to have stereotypies.

Molecular Function

This gene encodes a nucleic acid-binding protein that plays a role in a variety of nuclear processes, including pre-mRNA splicing and transcriptional regulation. The encoded protein forms a complex with the far upstream DNA element (FUSE) and FUSE-binding protein at the myelocytomatosis oncogene (MYC) promoter. This complex represses MYC transcription through the core-TFIIH basal transcription factor.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PUF60 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support - Salima El Chehadeh et al. (2016) No ASD, ID
3 Support - Karen J Low et al. (2017) No Stereotypy
4 Support - Zhou X et al. (2022) Yes -
5 Primary - Chengyan Li et al. (2024) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1588C>G p.Gln530Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1512C>T p.Gly504= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.892C>T p.Arg298Trp missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.901A>T p.Lys301Ter stop_gained De novo - - 27804958 Salima El Chehadeh et al. (2016)
c.1342C>T p.Arg448Ter stop_gained De novo - Simplex 39528574 Chengyan Li et al. (2024)
c.478_479del p.Met160ValfsTer18 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1342C>T p.Arg448Ter stop_gained De novo - Simplex 27804958 Salima El Chehadeh et al. (2016)
c.24+1G>C p.? splice_site_variant De novo - Simplex 27804958 Salima El Chehadeh et al. (2016)
c.1448T>C p.Val483Ala missense_variant De novo - Simplex 27804958 Salima El Chehadeh et al. (2016)
c.407_410delTCTA p.Ile136ThrfsTer31 frameshift_variant De novo - - 27804958 Salima El Chehadeh et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

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.

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."

10/1/2024
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.5286978590161

Ranking 1575/25841 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 0.84932485451145

Ranking 3622/18225 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 0.73490042776139

Ranking 1415/18665 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 0.099930402037357

Ranking 6139/20870 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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