Faculty Opinions recommendation of Detection of PKD1 and PKD2 Somatic Variants in Autosomal Dominant Polycystic Kidney Cyst Epithelial Cells by Whole-Genome Sequencing.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development of multiple cysts in the kidneys. It is often caused by pathogenic mutations in PKD1 and PKD2 genes that encode polycystin proteins. Although the molecular mechanisms for cystogenesis are not established, concurrent inactivating germline and somatic mutations in PKD1 and PKD2 have been previously observed in renal tubular epithelium (RTE). Methods: To further investigate the cellular recessive mechanism of cystogenesis in RTE, we conducted whole-genome DNA sequencing analysis to identify germline variants and somatic alterations in RTE of 90 unique kidney cysts obtained during nephrectomy from 24 unrelated participants. Results: Kidney cysts were overall genomically stable, with low burdens of somatic short mutations or large-scale structural alterations. Pathogenic somatic "second hit" alterations disrupting PKD1 or PKD2 were identified in 93% of the cysts. Of these, 77% of cysts acquired short mutations in PKD1 or PKD2; specifically, 60% resulted in protein truncations (nonsense, frameshift, or splice site) and 16.7% caused non-truncating mutations (missense, in-frame insertions, or deletions). Another ~18% of cysts acquired somatic chromosomal loss of heterozygosity (LOH) events encompassing PKD1 or PKD2 ranging from 2.6 to 81.3 Mb. 14.4% of these cysts harbored copy number neutral LOH events, while the other 3.3% had hemizygous chromosomal deletions. LOH events frequently occurred at chromosomal fragile sites, or in regions comprising chromosome microdeletion diseases/syndromes. Almost all somatic "second hit" alterations occurred at the same germline mutated PKD1/2 gene. Conclusions: These findings further support a cellular recessive mechanism for cystogenesis in ADPKD primarily caused by inactivating germline and somatic variants of PKD1 or PKD2 genes in kidney cyst epithelium.

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Celecoxib inhibits growth of human autosomal dominant polycystic kidney cyst-lining epithelial cells through the VEGF/Raf/MAPK/ERK signaling pathway

Molecular Biology Reports ◽

10.1007/s11033-012-1611-2 ◽

2012 ◽

Vol 39 (7) ◽

pp. 7743-7753 ◽

Cited By ~ 31

Author(s):

Tao Xu ◽

Nian-Song Wang ◽

Li-Li Fu ◽

Chao-Yang Ye ◽

Sheng-Qiang Yu ◽

...

Keyword(s):

Epithelial Cells ◽

Signaling Pathway ◽

Autosomal Dominant ◽

Erk Signaling ◽

Polycystic Kidney ◽

Kidney Cyst ◽

Autosomal Dominant Polycystic Kidney ◽

Cyst Lining

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Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing

Journal of the American Society of Nephrology ◽

10.1681/asn.2018050493 ◽

2018 ◽

Vol 29 (10) ◽

pp. 2593-2600 ◽

Cited By ~ 40

Author(s):

Matthew B. Lanktree ◽

Amirreza Haghighi ◽

Elsa Guiard ◽

Ioan-Andrei Iliuta ◽

Xuewen Song ◽

...

Keyword(s):

Liver Disease ◽

General Population ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Autosomal Dominant ◽

Incomplete Penetrance ◽

Whole Genome ◽

Polycystic Kidney ◽

Genome Sequences ◽

High Confidence

BackgroundEstimating the prevalence of autosomal dominant polycystic kidney disease (ADPKD) is challenging because of age-dependent penetrance and incomplete clinical ascertainment. Early studies estimated the lifetime risk of ADPKD to be about one per 1000 in the general population, whereas recent epidemiologic studies report a point prevalence of three to five cases per 10,000 in the general population.MethodsTo measure the frequency of high-confidence mutations presumed to be causative in ADPKD and autosomal dominant polycystic liver disease (ADPLD) and estimate lifetime ADPKD prevalence, we used two large, population sequencing databases, gnomAD (15,496 whole-genome sequences; 123,136 exome sequences) and BRAVO (62,784 whole-genome sequences). We used stringent criteria for defining rare variants in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5), and potential cystic disease modifiers; evaluated variants for quality and annotation; compared variants with data from an ADPKD mutation database; and used bioinformatic tools to predict pathogenicity.ResultsIdentification of high-confidence pathogenic mutations in whole-genome sequencing provided a lower boundary for lifetime ADPKD prevalence of 9.3 cases per 10,000 sequenced. Estimates from whole-genome and exome data were similar. Truncating mutations in ADPLD genes and genes of potential relevance as cyst modifiers were found in 20.2 cases and 103.9 cases per 10,000 sequenced, respectively.ConclusionsPopulation whole-genome sequencing suggests a higher than expected prevalence of ADPKD-associated mutations. Loss-of-function mutations in ADPLD genes are also more common than expected, suggesting the possibility of unrecognized cases and incomplete penetrance. Substantial rare variation exists in genes with potential for phenotype modification in ADPKD.

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Faculty Opinions recommendation of Combination of whole genome sequencing, linkage, and functional studies implicates a missense mutation in titin as a cause of autosomal dominant cardiomyopathy with features of left ventricular noncompaction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726741600.793535813 ◽

2017 ◽

Author(s):

WH Wilson Tang

Keyword(s):

Whole Genome Sequencing ◽

Missense Mutation ◽

Genome Sequencing ◽

Autosomal Dominant ◽

Left Ventricular ◽

Whole Genome ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Functional Studies

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Effective variant filtering and expected candidate variant yield in studies of rare human disease

npj Genomic Medicine ◽

10.1038/s41525-021-00227-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Brent S. Pedersen ◽

Joe M. Brown ◽

Harriet Dashnow ◽

Amelia D. Wallace ◽

Matt Velinder ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Rare Disease ◽

Genome Sequencing ◽

Autosomal Dominant ◽

De Novo ◽

Autosomal Dominant Inheritance ◽

Compound Heterozygous ◽

Whole Genome ◽

Dominant Inheritance ◽

Family Based

AbstractIn studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

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Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease

Nature Communications ◽

10.1038/s41467-021-24799-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hao Ding ◽

Linda Xiaoyan Li ◽

Peter C. Harris ◽

Junwei Yang ◽

Xiaogang Li

Keyword(s):

Kidney Disease ◽

Epithelial Cells ◽

Polycystic Kidney Disease ◽

Extracellular Vesicles ◽

Autosomal Dominant ◽

Therapeutic Potential ◽

Polycystic Kidney ◽

Renal Epithelial Cells ◽

Autosomal Dominant Polycystic Kidney ◽

Cyst Growth

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. However, if and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. Here we address this question with a “cystic extracellular vesicles/exosomes theory”. We show that cystic cell derived extracellular vesicles and urinary exosomes derived from ADPKD patients promote cyst growth in Pkd1 mutant kidneys and in 3D cultures. This is achieved by: 1) downregulation of Pkd1 gene expression and upregulation of specific miRNAs, resulting in the activation of PKD associated signaling pathways in recipient renal epithelial cells and tissues; 2) the activation of fibroblasts; and 3) the induction of cytokine expression and the recruitment of macrophages to increase renal inflammation in cystic kidneys. Inhibition of exosome biogenesis/release with GW4869 significantly delays cyst growth in aggressive and milder ADPKD mouse models, suggesting that targeting exosome secretion has therapeutic potential for ADPKD.

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