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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KB is supported by an Enterprise Partnership Scheme Fellowship Award (2019) from The Irish Research Council, in conjunction with Punchestown Kidney Research Fund (EPSPD/2019/213). The authors also acknowledge funding received from the Beaumont Hospital Foundation, the Royal Irish Academy and the Royal College of Surgeons in Ireland. SC is supported by the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland. We also acknowledge that this work would not be possible without the participation of the consenting patients and their families.
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Benson, K.A., Murray, S.L., Senum, S.R. et al. The genetic landscape of polycystic kidney disease in Ireland. Eur J Hum Genet (2021). https://doi.org/10.1038/s41431-020-00806-5