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The genetic landscape of polycystic kidney disease in Ireland

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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Fig. 1: Detection rates of molecular causes of PKD.
Fig. 2: Number and type of PKD1 and PKD2 AD pathogenic variants detected.
Fig. 3: Diagnostic PKD1 variants detected using custom next-generation sequencing pipeline.
Fig. 4: Kaplan Meier survival graph showing time to ESKD.

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Acknowledgements

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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Correspondence to Gianpiero L. Cavalleri or Peter Conlon.

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Supplementary Information

Supplementary Table 1: Roche HeatSeq gene list

Supplementary Table 2: ACMG guidelines interpretation method

Supplementary Table 3: Supplementary Table 3: Genetic Diagnosis in patients in which a disease-causing variant of PKD was identified

Supplementary Table 4: KING and refined IBD results

Supplementary Table 5: Kinship scores and inferred relationships

Supplementary Table 6: LOD scores

Supplementary Table 7: ACMG and Mayo Clinic classifications assigned to each variant from the Rossetti dataset

Supplementary Table 8: Additional variants which satisfied the ACMG guidelines for variant pathogenicity

Supplementary Table 9: Clinical details of patients without a molecular diagnosis

Supplementary Table 10: Correponding protein domins for variants listed in Figure 2

Supplementary Table 11: Genetic scoring of nontruncating PKD1 and PKD2 variants scored as VUS by the ACMG classification employing the Mayo Research Mutation Classification Algorithm

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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

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