Human Gene Module / Chromosome 16 / PKD1

PKD1polycystin 1, transient receptor potential channel interacting

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
9 / 9
Rare Variants / Common Variants
32 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
16p13.3
Associated Disorders
-
Relevance to Autism

A de novo missense variant with a CADD score > 25 was identified in the PKD1 gene in a Korean ASD proband in Kim et al., 2024; this gene was subsequently classified as an ASD candidate gene in males following a combined TADA analysis consisting of the Korean ASD cohort described in Kim et al., 2024 in addition to the Simons Simplex Collection and the SPARK cohort. A number of de novo variants in this gene were previously reported in ASD probands from the Autism Sequencing Consortium, the Simons Simplex Collection, the SPARK cohort, and the MSSNG cohort, including two de novo loss-of-function variants and two de novo missense variants with CADD scores > 25 that were identified in SPARK probands (De Rubeis et al., 2014; Iossifov et al., 2014; Yuen et al., 2017; Feliciano et al., 2019; Satterstrom et al., 2020; Zhou et al., 2022; Fu et al., 2022; Trost et al., 2022).

Molecular Function

This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PKD1 (9 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 The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P 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 Support - Zhou X et al. (2022) Yes -
7 Support - Fu JM et al. (2022) Yes -
8 Support - Trost B et al. (2022) Yes -
9 Primary - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (32)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.7605C>G p.Tyr2535Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.9398-2A>G p.? splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.8716G>A p.Gly2906Ser missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.9484C>T p.Arg3162Cys missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.7206A>G p.Arg2402= synonymous_variant De novo - - 35982160 Fu JM et al. (2022)
c.1375C>T p.Arg459Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.11975C>T p.Ala3992Val missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.7846G>C p.Val2616Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8077G>A p.Ala2693Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8593C>T p.Arg2865Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8611G>A p.Ala2871Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3333C>T p.Phe1111= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.4269C>T p.Pro1423= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3876C>T p.Phe1292= synonymous_variant De novo - - 36368308 Trost B et al. (2022)
c.10377C>T p.Tyr3459= synonymous_variant De novo - - 36368308 Trost B et al. (2022)
c.6594G>A p.Pro2198= synonymous_variant De novo - - 31452935 Feliciano P et al. (2019)
c.2843G>T p.Gly948Val missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.2722G>A p.Val908Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.9006G>A p.Ser3002= synonymous_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2644G>A p.Val882Met missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.4090C>T p.Arg1364Cys missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.5738C>T p.Ala1913Val missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.8654G>A p.Arg2885Gln missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.8034C>T p.Leu2678= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.6936G>A p.Ala2312= synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.13_21del p.Ala5_Ala7del inframe_deletion De novo - Simplex 35982159 Zhou X et al. (2022)
c.5667C>T p.Gly1889= synonymous_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1776C>T p.Ala592= synonymous_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.3111A>G p.Leu1037= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4656C>T p.Val1552= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.7656C>T p.Ala2552= synonymous_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.11203G>A p.Val3735Ile missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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.

10/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.56409865447168

Ranking 1279/25841 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 0.99990533199147

Ranking 671/18225 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 0.95082276781922

Ranking 18642/18665 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 0.21221303035639

Ranking 4067/20870 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
CNVs associated with PKD1(1 CNVs)
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16p13.3 71 Deletion-Duplication 101  /  542
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