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

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

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(7), P. 555 - 573

Published: Feb. 16, 2024

Language: Английский

Citations

45
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

et al.

Kidney International, Journal Year: 2025, Volume and Issue: 107(2), P. S1 - S239

Published: Jan. 21, 2025

Language: Английский

Citations

6
Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis DOI Creative Commons

Hugo Lemoine,

Loann Raud, François Foulquier

et al.

The American Journal of Human Genetics, Journal Year: 2022, Volume and Issue: 109(8), P. 1484 - 1499

Published: July 26, 2022

Language: Английский

Citations

46
A spectrum of recessiveness among Mendelian disease variants in UK Biobank DOI Creative Commons
Alison R. Barton, Margaux L.A. Hujoel, Ronen E. Mukamel

et al.

The American Journal of Human Genetics, Journal Year: 2022, Volume and Issue: 109(7), P. 1298 - 1307

Published: May 31, 2022

Language: Английский

Citations

44
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

et al.

Journal of the American Society of Nephrology, Journal Year: 2023, Volume and Issue: 34(12), P. 2039 - 2050

Published: Oct. 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.

Language: Английский

Citations

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

Meiqin Jiang,

Vivek Reddy Palicharla,

Darcie J. Miller

et al.

Cell Research, Journal Year: 2023, Volume and Issue: 33(4), P. 288 - 298

Published: Feb. 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.

Language: Английский

Citations

26
Phenotypic Heterogeneity of ADTKD-MUC1 Diagnosed Using VNtyper, a Novel Genetic Technique DOI
Jessica Kachmar, Hassan Saei, Vincent Morinière

et al.

American Journal of Kidney Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

1
Rare disease gene association discovery in the 100,000 Genomes Project DOI Creative Commons
Valentina Cipriani, Letizia Vestito, Emma Magavern

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 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.

Language: Английский

Citations

1
Autosomal Dominant Polycystic Kidney Disease DOI
Fouad T. Chebib, Christian Hanna, Peter C. Harris

et al.

JAMA, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

Importance Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of cysts and the most common inherited disorder worldwide. ADPKD accounts for 5% to 10% failure in US Europe, its prevalence 9.3 per 10 000 individuals. Observations typically diagnosed individuals aged 27 42 years primarily caused pathogenic variants PKD1 (78%) or PKD2 (15%) genes. Most persons with have an affected parent, but de novo suggested 25% families. More than 90% patients older 35 hepatic cysts, which may cause abdominal discomfort occasionally require medical surgical intervention. Hypertension affects 70% 80% ADPKD, approximately 9% 14% develop intracranial aneurysms, a rupture rate 0.57 1000 patient-years. Approximately 50% replacement therapy 62 age. The severity can be quantified using Mayo Imaging Classification (MIC), stratifies based on total volume adjusted height age ranges from 1A 1E. Patients MIC 1C 1E larger kidneys because more rapid growth (6%-10% year) compared those 1B (1%-5% earlier progression therapy, occurs at mean 58.4 1C, 52.5 1D, 43.4 Optimal management includes systolic blood pressure lower 120 mm Hg patients, 110/75 who estimated glomerular filtration (eGFR) greater 60 mL/min/1.73 m 2 are younger 50 years, dietary sodium restriction (<2000 mg/d), weight management, adequate hydration (>2.5 L daily). vasopressin type receptor antagonist tolvaptan reduces annual eGFR decline 0.98 1.27 indicated 3 year slow delay onset failure. Conclusion genetic worldwide cysts. hypertension liver aneurysms. First-line treatment control, hydration. Tolvaptan high risk

Language: Английский

Citations

1
Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease DOI Creative Commons
Laura R. Claus, Chuan Chen,

Jennifer L. Stallworth

et al.

Kidney International, Journal Year: 2023, Volume and Issue: 104(5), P. 995 - 1007

Published: Aug. 19, 2023

Language: Английский

Citations

17