Benson Katherine A, Murray Susan L, Senum Sarah R, Elhassan Elhussein, Conlon Eoin T, Kennedy Claire, Conlon Shane, Gilbert Edmund, Connaughton Dervla, O'Hara Paul, Khamis Sarah, Cormican Sarah, Brody Lawrence C, Molloy Anne M, Lynch Sally Ann, Casserly Liam, Griffin Matthew D, Carton Robert, Yachnin Kevin, Harris Peter C, Cavalleri Gianpiero L, Conlon Peter
School of Pharmacy and Biomolecular Science, Royal College of Surgeons in Ireland, Dublin, Ireland.
Department of Nephrology, Beaumont Hospital, Dublin, Ireland.
Eur J Hum Genet. 2021 May;29(5):827-838. doi: 10.1038/s41431-020-00806-5. Epub 2021 Jan 16.
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.
多囊肾病（PKD）是最常见的孟德尔遗传性肾病类型。其特征是出现充满液体的肾囊肿，导致肾功能逐渐丧失，最终需要进行肾脏替代治疗或肾移植。爱尔兰是进行PKD基因研究的一个重要地区，因为传统上家庭规模较大且人口相对同质。通过对169名患者的队列研究，我们首次描述了爱尔兰PKD的基因图谱，比较了有分子诊断和无分子诊断患者的临床特征，并将疾病严重程度与常染色体显性致病变异型相关联。使用包括靶向二代测序在内的多种分子遗传学工具，根据所使用的变异分类指南（分别为美国医学遗传学与基因组学学会（ACMG）或梅奥诊所指南），我们报告爱尔兰PKD患者的诊断率为71% - 83%。我们已梳理出一系列爱尔兰常染色体显性PKD致病变异，包括36种新变异。我们说明了携带相同常染色体显性致病变异的明显无关个体如何极有可能从共同祖先那里继承了该变异。我们强调了在PKD中实施ACMG变异致病性解读指南所涉及的问题，这些问题对临床遗传学具有重要意义。
