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

и другие.

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(19)

Опубликована: Авг. 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.

Язык: Английский

Emerging mechanistic understanding of cilia function in cellular signalling DOI
Keren I. Hilgendorf, Benjamin R. Myers, Jeremy F. Reiter

и другие.

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(7), С. 555 - 573

Опубликована: Фев. 16, 2024

Язык: Английский

Процитировано

48
KDIGO 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) DOI Creative Commons
Olivier Devuyst, Curie Ahn, Thijs R.M. Barten

и другие.

Kidney International, Год журнала: 2025, Номер 107(2), С. S1 - S239

Опубликована: Янв. 21, 2025

Язык: Английский

Процитировано

7
A spectrum of recessiveness among Mendelian disease variants in UK Biobank DOI Creative Commons
Alison R. Barton, Margaux L.A. Hujoel, Ronen E. Mukamel

и другие.

The American Journal of Human Genetics, Год журнала: 2022, Номер 109(7), С. 1298 - 1307

Опубликована: Май 31, 2022

Язык: Английский

Процитировано

47
Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis DOI Creative Commons

Hugo Lemoine,

Loann Raud, François Foulquier

и другие.

The American Journal of Human Genetics, Год журнала: 2022, Номер 109(8), С. 1484 - 1499

Опубликована: Июль 26, 2022

Язык: Английский

Процитировано

46
The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease DOI Creative Commons
Neera K. Dahl, Michelle S. Bloom, Fouad T. Chebib

и другие.

Journal of the American Society of Nephrology, Год журнала: 2023, Номер 34(12), С. 2039 - 2050

Опубликована: Окт. 5, 2023

Significance Statement Accurate diagnosis of a patient's underlying cause CKD can influence management and ultimately overall health. The single-arm, interventional, prospective Renasight Clinical Application, Review, Evaluation study assessed the utility genetic testing with 385 gene kidney disease panel on 1623 patients CKD. Among 20.8% who had positive findings, half resulted in new or reclassified diagnosis. In addition, change because was reported for 90.7% including treatment changes 32.9%. These findings demonstrate that has significant effect both management. Background Genetic recently been shown to have diagnostic many predicted implications clinical management, but its not prospectively evaluated. Methods RenaCARE (ClinicalTrials.gov NCT05846113) is prospective, multicenter evaluated broad, (the TM test) adult recruited from 31 US-based community academic medical centers. Patient history were collected at enrollment. Physician responses questionnaires regarding patient categorization before 1 month after return test results. Changes assessed. Results Of 13 predefined categories (ages, 18–96; median, 55 years), ( n =338) spanning 54 genes. Positive provided prior 48.8% those patients. Physicians results altered finding, plan, which 32.9% these Conclusions CKD-focused substantially refined diagnoses widespread appropriate strategies. data support broader integration panels tests into care paradigm Trial registry name registration number ClinicalTrials.gov, NCT05846113.

Язык: Английский

Процитировано

42
Human IFT-A complex structures provide molecular insights into ciliary transport DOI Creative Commons

Meiqin Jiang,

Vivek Reddy Palicharla,

Darcie J. Miller

и другие.

Cell Research, Год журнала: 2023, Номер 33(4), С. 288 - 298

Опубликована: Фев. 13, 2023

Abstract Intraflagellar transport (IFT) complexes, IFT-A and IFT-B, form bidirectional trains that move along the axonemal microtubules are essential for assembling maintaining cilia. Mutations in IFT subunits lead to numerous ciliopathies involving multiple tissues. However, how complexes assemble mediate cargo lacks mechanistic understanding due missing high-resolution structural information of holo-complexes. Here we report cryo-EM structures human presence absence TULP3 at overall resolutions 3.0–3.9 Å. adopts a “lariat” shape with interconnected core peripheral linked by structurally vital zinc-binding domains. TULP3, adapter, interacts through its N-terminal region, interface mutations disrupt transport. We also determine molecular impacts disease on complex formation ciliary Our work reveals architecture, sheds light train formation, enables rationalization ciliopathies.

Язык: Английский

Процитировано

26
Rare disease gene association discovery in the 100,000 Genomes Project DOI Creative Commons
Valentina Cipriani, Letizia Vestito, Emma Magavern

и другие.

Nature, Год журнала: 2025, Номер unknown

Опубликована: Фев. 26, 2025

Abstract Up to 80% of rare disease patients remain undiagnosed after genomic sequencing 1 , with many probably involving pathogenic variants in yet be discovered disease–gene associations. To search for such associations, we developed a variant gene burden analytical framework Mendelian diseases, and applied it protein-coding from whole-genome 34,851 cases their family members recruited the 100,000 Genomes Project 2 . A total 141 new associations were identified, including five which independent evidence was recently published. Following silico triaging clinical expert review, 69 prioritized, 30 could linked existing experimental evidence. The strongest overall genetic monogenic diabetes known β cell regulator 3,4 UNC13A schizophrenia GPR17 epilepsy RBFOX3 Charcot–Marie–Tooth ARPC3 anterior segment ocular abnormalities POMK Further confirmation these other lead numerous diagnoses, highlighting impact large-scale statistical approaches association discovery.

Язык: Английский

Процитировано

2
Global analysis of urinary extracellular vesicle small RNAs in autosomal dominant polycystic kidney disease DOI Creative Commons
Hamad Ali, Md. Zubbair Malik, Mohamed Abu‐Farha

и другие.

The Journal of Gene Medicine, Год журнала: 2024, Номер 26(2)

Опубликована: Фев. 1, 2024

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic renal progressing to end‐stage disease. There a pressing need for identification of early ADPKD biomarkers enable timely intervention and development effective therapeutic approaches. Here, we profiled human urinary extracellular vesicles small RNAs by RNA sequencing in patients with compared their differential expression considering healthy control individuals identify dysregulated analyze downstream interaction gain insight about molecular pathophysiology. Methods This cross‐sectional study where urine samples were collected from total 23 PKD1‐ADPKD 28 individuals. Urinary purified, was isolated sequenced. Differentially expressed Small identified functional enrichment analysis critical miRNAs performed driver genes affected pathways. Results miR‐320b, miR‐320c, miR‐146a‐5p, miR‐199b‐3p, miR‐671‐5p, miR‐1246, miR‐8485, miR‐3656, has_piR_020497, has_piR_020496 has_piR_016271 significantly upregulated patient miRNA‐29c downregulated. Five ‘driver’ target ( FBRS , EDC3 FMNL3 CTNNBIP1 KMT2A ) identified. Conclusions The findings present make significant contributions understanding pathogenesis novel potential drug targets aimed at slowing progression ADPKD.

Язык: Английский

Процитировано

9
Monoallelic pathogenic IFT140 variants are a common cause of autosomal dominant polycystic kidney disease–spectrum phenotype DOI Creative Commons
Chiara Dordoni, Letizia Zeni, Diego Toso

и другие.

Clinical Kidney Journal, Год журнала: 2024, Номер 17(2)

Опубликована: Фев. 1, 2024

ABSTRACT Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder, characterized by development and enlargement of cysts, eventually leading to end-stage (ESKD). Pathogenic variants in PKD1 PKD2 genes are major cause ADPKD; additional rare GANAB, DNAJB11, ALG5 ALG9 have been found a minority ADPKD patients. More recently, significant number families linked monoallelic IFT140 gene. Methods In this retrospective study, we tested prevalence known causative ADPKD-spectrum phenotype, including PKD1, PKD2, ALG5, ALG genes, cohort 129 patients who consecutively underwent genetic testing single centre Italy. Genetic utilized combination targeted next-generation sequencing, long-range polymerase chain reaction, Sanger sequencing multiplex ligation-dependent probe amplification. Clinical evaluation was conducted through renal function imaging features, ultrasonography, computer tomography magnetic resonance imaging. Results Of enrolled patients, 86 (66.7%) had pathogenic 28 (21.7%) loss gene were 3 unrelated (2.3%), no other 12 (9.3%) remained genetically unresolved (ADPKD-GUR). Familial clinical screening index with due an variant (ADPKD-IFT140) allowed identification eight affected relatives. 11 ADPKD-IFT140 phenotype mild late-onset PKD, large cysts limited insufficiency. Extrarenal manifestations, liver rarely seen. Conclusion Our data suggest third Italy, usually associated atypical cystic disease.

Язык: Английский

Процитировано

8
Phenotypic Heterogeneity of ADTKD-MUC1 Diagnosed Using VNtyper, a Novel Genetic Technique DOI
Jessica Kachmar, Hassan Saei, Vincent Morinière

и другие.

American Journal of Kidney Diseases, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

1