Cogal Andrea G, Arroyo Jennifer, Shah Ronak Jagdeep, Reese Kalina J, Walton Brenna N, Reynolds Laura M, Kennedy Gabrielle N, Seide Barbara M, Senum Sarah R, Baum Michelle, Erickson Stephen B, Jagadeesh Sujatha, Soliman Neveen A, Goldfarb David S, Beara-Lasic Lada, Edvardsson Vidar O, Palsson Runolfur, Milliner Dawn S, Sas David J, Lieske John C, Harris Peter C
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
Kidney Int Rep. 2021 Sep 8;6(11):2862-2884. doi: 10.1016/j.ekir.2021.08.033. eCollection 2021 Nov.
Because of phenotypic overlap between monogenic urinary stone diseases (USD), gene-specific analyses can result in missed diagnoses. We used targeted next generation sequencing (tNGS), including known and candidate monogenic USD genes, to analyze suspected primary hyperoxaluria (PH) or Dent disease (DD) patients genetically unresolved (negative; N) after Sanger analysis of the known genes. Cohorts consisted of 285 PH (PHN) and 59 DD (DDN) families.
Variants were assessed using disease-specific and population databases plus variant assessment tools and categorized using the American College of Medical Genetics (ACMG) guidelines. Prior Sanger analysis identified 47 novel PH or DD gene pathogenic variants.
Screening by tNGS revealed pathogenic variants in 14 known monogenic USD genes, accounting for 45 families (13.1%), 27 biallelic and 18 monoallelic, including 1 family with a copy number variant (CNV). Recurrent genes included the following: (n = 13) (n = 8), (n = 4) (n = 3), (n = 3), (n = 2), (n = 2), (n = 2), and (n = 2), whereas and and missed CNVs in the PH genes and accounted for 1 pedigree each. Of the 48 defined pathogenic variants, 27.1% were truncating and 39.6% were novel. Most patients were diagnosed before 18 years of age (76.1%), and 70.3% of biallelic patients were homozygous, mainly from consanguineous families.
Overall, in patients suspected of DD or PH, 23.9% and 7.3% of cases, respectively, were caused by pathogenic variants in other genes. This study shows the value of a tNGS screening approach to increase the diagnosis of monogenic USD, which can optimize therapies and facilitate enrollment in clinical trials.
由于单基因尿路结石疾病(USD)之间存在表型重叠,基因特异性分析可能会导致漏诊。我们使用靶向新一代测序(tNGS),包括已知和候选的单基因USD基因,对已知基因进行桑格分析后基因检测结果未明确(阴性;N)的疑似原发性高草酸尿症(PH)或丹特病(DD)患者进行基因分析。研究队列包括285个PH(PHN)和59个DD(DDN)家庭。
使用疾病特异性和人群数据库以及变异评估工具对变异进行评估,并根据美国医学遗传学学会(ACMG)指南进行分类。先前的桑格分析确定了47个新的PH或DD基因致病变异。
通过tNGS筛查发现14个已知单基因USD基因存在致病变异,涉及45个家庭(13.1%),其中27个为双等位基因变异,18个为单等位基因变异,包括1个存在拷贝数变异(CNV)的家庭。常见基因包括以下几种:(n = 13)(n = 8),(n = 4)(n = 3),(n = 3),(n = 2),(n = 2),(n = 2),以及(n = 2),而和以及PH基因和中的漏检CNV各占1个家系。在48个已确定的致病变异中,27.1%为截短变异,39.6%为新变异。大多数患者在18岁之前被诊断出来(76.1%),70.3%的双等位基因患者为纯合子,主要来自近亲家庭。
总体而言,在疑似DD或PH的患者中,分别有23.9%和7.3%的病例是由其他基因的致病变异引起的。这项研究显示了tNGS筛查方法在增加单基因USD诊断方面的价值,这可以优化治疗方案并促进临床试验的入组。