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Published on: June 23, 2015
The genetic landscape of polycystic kidney disease in Ireland
Katherine A Benson1, Susan L Murray2, Sarah R Senum3
1School of Pharmacy and Biomolecular Science, Royal College of Surgeons in Ireland, Dublin, Ireland.
Insights
This study details the genetic causes of Polycystic Kidney Disease (PKD) in Ireland, identifying numerous genetic variants and achieving high diagnostic rates. Findings improve understanding of PKD genetics and clinical implications.
Area of Science:
- Genetics
- Nephrology
- Medical Research
Background:
- Polycystic kidney diseases (PKDs) are common inherited renal diseases characterized by cyst formation and progressive kidney function loss.
- Ireland's homogenous population and large family sizes offer a unique setting for genetic studies of PKD.
- Understanding the genetic landscape of PKD is crucial for diagnosis and management.
Purpose of the Study:
- To investigate the genetic landscape of Polycystic Kidney Disease (PKD) in an Irish cohort.
- To compare clinical features between patients with and without a molecular diagnosis.
- To correlate disease severity with autosomal dominant pathogenic variant types and assess diagnostic rates.
Main Methods:
- Analysis of a cohort of 169 Irish patients with PKD.
- Utilized molecular genetic tools, including targeted next-generation sequencing.
- Applied variant classification guidelines (ACMG and Mayo Clinic) for pathogenicity interpretation.
Main Results:
- Achieved diagnostic rates of 71-83% in Irish PKD patients, depending on classification guidelines used.
- Catalogued a spectrum of autosomal dominant PKD pathogenic variants, including 36 novel variants.
- Demonstrated common ancestry for individuals with the same pathogenic variant and highlighted issues with ACMG guideline implementation.
Conclusions:
- This study provides the first comprehensive genetic profile of PKD in Ireland.
- High diagnostic rates were achieved, improving molecular diagnosis for Irish PKD patients.
- Findings have significant implications for clinical genetics, variant interpretation, and understanding PKD inheritance patterns.
Abstract:
Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71-83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.
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