Atypical splicing variants in PKD1 explain most undiagnosed typical familial ADPKD DOI Creative Commons

Yvonne Hort,

Patricia A. Sullivan,

Laura Wedd

et al.

npj Genomic Medicine, Journal Year: 2023, Volume and Issue: 8(1)

Published: July 7, 2023

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of failure and primarily associated with PKD1 or PKD2. Approximately 10% patients remain undiagnosed after standard genetic testing. We aimed to utilise short long-read genome sequencing RNA studies investigate families. Patients typical ADPKD phenotype diagnostics were recruited. Probands underwent short-read sequencing, PKD2 coding non-coding analyses then genome-wide analysis. Targeted investigated variants suspected impact splicing. Those Oxford Nanopore Technologies sequencing. From over 172 probands, 9 met inclusion criteria consented. A diagnosis was made in 8 (89%) families on prior Six had impacting splicing, five regions PKD1. Short-read identified novel branchpoint, AG-exclusion zone missense generating cryptic splice sites a deletion causing critical intron shortening. Long-read confirmed one family. Most have splice-impacting describe pragmatic method for diagnostic laboratories assess validate splicing through targeted studies.

Language: Английский

Importance of IFT140 in Patients with Polycystic Kidney Disease Without a Family History DOI Creative Commons
Takuya Fujimaru, Takayasu Mori, Akinari Sekine

et al.

Kidney International Reports, Journal Year: 2024, Volume and Issue: 9(9), P. 2685 - 2694

Published: July 16, 2024

Recently, the monoallelic loss-of-function IFT140 variant was identified as a causative gene for autosomal dominant polycystic kidney disease (ADPKD). In patients with kidneys who have positive family history, >90% pathogenic variants in

Language: Английский

Citations

4
Quantifying variant contributions in cystic kidney disease using national-scale whole genome sequencing DOI Creative Commons
Omid Sadeghi‐Alavijeh, Melanie Chan, Gabriel Doctor

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(19)

Published: Aug. 27, 2024

BACKGROUNDCystic kidney disease (CyKD) is a predominantly familial in which gene discovery has been led by family-based and candidate studies, an approach that susceptible to ascertainment other biases.METHODSUsing whole-genome sequencing data from 1,209 cases 26,096 ancestry-matched controls participating the 100,000 Genomes Project, we adopted hypothesis-free approaches generate quantitative estimates of risk for each genetic contributor CyKD, across genes, variant types allelic frequencies.RESULTSIn 82.3% cases, qualifying potentially disease-causing rare established was found. There enrichment coding, splicing, structural variants known CyKD with statistically significant gene-based signals COL4A3 (monoallelic) PKHD1. Quantification (with replication separate UK Biobank study) revealed substantially lower associated genes more recently autosomal dominant polycystic disease, odds ratios some below what might usually be regarded as necessary classical Mendelian inheritance. Meta-analysis common did not reveal associations, but suggested this category variation contributes 3%-9% heritability European ancestries.CONCLUSIONBy providing unbiased quantification effects per gene, research suggests all contributors are equally likely manifest trait families. This information may inform testing counseling clinic.

Language: Английский

Citations

4
Autosomal Dominant Polycystic Kidney Disease DOI
Maria Lourdes Gonzalez Suarez, Silvia Titan, Neera K. Dahl

et al.

Advances in Kidney Disease and Health, Journal Year: 2024, Volume and Issue: 31(6), P. 496 - 503

Published: Nov. 1, 2024

Language: Английский

Citations

4
Autosomal dominant tubulointerstitial kidney disease: A review DOI Creative Commons
Martina Živná, Kendrah Kidd, Veronika Barešová

et al.

American Journal of Medical Genetics Part C Seminars in Medical Genetics, Journal Year: 2022, Volume and Issue: 190(3), P. 309 - 324

Published: Sept. 1, 2022

The clinical characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD) include bland urinary sediment, slowly progressive chronic (CKD) with many patients reaching end stage renal (ESRD) between age 20 and 70 years, inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause CKD. Pathogenic variants UMOD, MUC1, REN are the most common causes ADTKD. ADTKD-UMOD also associated hyperuricemia gout. ADTKD-REN often presents childhood mild hypotension, CKD, hyperkalemia, acidosis, anemia. ADTKD-MUC1 present only This review describes pathophysiology, genetics, manifestation, diagnosis for ADTKD, an emphasis on testing counseling suggestions patients.

Language: Английский

Citations

17
Atypical splicing variants in PKD1 explain most undiagnosed typical familial ADPKD DOI Creative Commons

Yvonne Hort,

Patricia A. Sullivan,

Laura Wedd

et al.

npj Genomic Medicine, Journal Year: 2023, Volume and Issue: 8(1)

Published: July 7, 2023

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of failure and primarily associated with PKD1 or PKD2. Approximately 10% patients remain undiagnosed after standard genetic testing. We aimed to utilise short long-read genome sequencing RNA studies investigate families. Patients typical ADPKD phenotype diagnostics were recruited. Probands underwent short-read sequencing, PKD2 coding non-coding analyses then genome-wide analysis. Targeted investigated variants suspected impact splicing. Those Oxford Nanopore Technologies sequencing. From over 172 probands, 9 met inclusion criteria consented. A diagnosis was made in 8 (89%) families on prior Six had impacting splicing, five regions PKD1. Short-read identified novel branchpoint, AG-exclusion zone missense generating cryptic splice sites a deletion causing critical intron shortening. Long-read confirmed one family. Most have splice-impacting describe pragmatic method for diagnostic laboratories assess validate splicing through targeted studies.

Language: Английский

Citations

11