Facilitating personalized medicine of monogenic stone patients by genetic characterization

通过遗传特征促进单基因结石患者的个性化医疗

• 批准号: 10153916
• 负责人: Peter C. Harris
• 金额: $ 19.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153916
• 关键词: Accounting; Address; Affect; Alleles; Biochemical; Candidate Disease Gene; Child; Clinical; Clinical Research; Clinical Trials; Counseling; Cystinuria; Data; Dent Disease; Developed Countries; Development; Diagnosis; Diagnostic; Dideoxy Chain Termination DNA Sequencing; Disease; Eligibility Determination; Enzymes; Excretory function; Family; Funding; Genes; Genetic; Genetic Databases; Genetic Screening; Genotype; Health Care Costs; Heritability; Hospitalization; Individual; Infrastructure; Inherited; Kidney Calculi; Kidney Diseases; Kidney Failure; Knowledge; Lead; Messenger RNA; Metabolic Pathway; Methods; Minerals; Modification; Molecular; Molecular Chaperones; Molecular Conformation; Molecular Diagnosis; Morbidity - disease rate; Mutate; Mutation; Natural History; Nephrocalcinosis; Nephrolithiasis; Nephrology; Operative Surgical Procedures; Other Genetics; Oxalates; Pain; Pathogenicity; Patient Recruitments; Patients; Phenotype; Physicians; Population; Primary Hyperoxaluria; Proteins; Research Personnel; Services; Site; Small RNA; Specific qualifier value; Testing; Therapeutic; Urinary Calculi; Variant; Work; adenine phosphoribosyltransferase deficiency; base; bioinformatics pipeline; causal variant; clinical database; clinical trial readiness; cohort; early screening; exome sequencing; experience; gene panel; genetic analysis; genetic variant; genotyped patients; hypercalciuria; improved; insight; lost work time; next generation sequencing; novel therapeutic intervention; novel therapeutics; patient population; patient stratification; patient variability; personalized medicine; prognostic; recruit; screening; small molecule; targeted treatment; translational study; treatment trial; urinary

Facilitating personalized medicine of monogenic stone patients by genetic characterization Next generation sequencing (NGS), including employing a targeted (t)NGS panel of known and candidate genes, is highlighting that severe, inherited forms of urinary stone disease (USD) are more common than previously appreciated, with ~40 genes now implicated. These monogenic USD are at the forefront of the application of personalized medicine in nephrology. Treatments can target enzymes/mRNAs encoding key steps in the defective metabolic pathway that lead to accumulation of harmful intermediates or via chaperone treatments to help fold and correctly traffic the mutated proteins. Genic and allelic information is increasingly a prerequisite for involvement in these targeted clinical trials. Over the past 10 years, the Rare Kidney Stone Consortium (RKSC) has focused on recruiting and characterizing patient populations with monogenic USD with the aims to understand the natural history of the disorders, conduct genotype/phenotype studies, and categorize patients for clinical studies. This initially involved Sanger sequencing but more recently tNGS with a ~100 gene panel. As part of this screening, patients presumed to have either primary hyperoxaluria (PH) or Dent disease (two common USD), but without mutations in the canonical genes for these disorders by Sanger sequencing, were screened on the panel. Out of 297 analyzed patients, a monogenic cause was detected in 30 cases (10.1%), with mutations identified in 11 different genes. In the past year, all RKSC recruited patients have been primarily genetically screened employing this tNGS approach and of 102 families screened 33 (32.4%) have been genetically resolved with 8 different genes identified. Interestingly, in ~15% of cases genetic complexity was identified with an additional likely pathogenic variant in a second monogenic gene. Unfortunately, funding for the RKSC was recently lost but we plan to keep the consortium intact and here propose to genetically characterize monogenic USD recruited through the RKSC groups, primarily to identify patients for inclusion in clinical trials. The proposal has two specific aims: 1. Genotype patients with a phenotype consistent with a monogenic form of nephrolithiasis or nephrocalcinosis using global NGS approaches and 2. Characterize and analyze the array of variants beyond the causative gene in monogenic stone patients. The project has co-PIs, one an expert in clinical and biochemical aspects of USD (Dr. Lieske), and one an expert in the genetics of monogenic kidney diseases (Dr. Harris). Tested tNGS approached will be employed along with a developed and proven bioinformatics pipeline to identify likely causative variants. These results will be returned to the referring physician, with safeguards of counseling and variant conformation, to provide diagnostic information, to allow personalized treatment, and encourage clinical trial recruitment. The accumulated knowledge of gene variants and variant combinations derived for the study will allow for better understanding of these diseases and provide insights into genetic factors causing phenotypic modification.

通过遗传表征促进单基石患者的个性化药物 下一代测序（NGS），包括采用已知和候选者的目标（t）NGS面板 基因强调，严重的遗传形式的尿石病（USD）比 以前被欣赏，现在涉及约40个基因。这些单基金在 个性化医学在肾脏病中的应用。治疗可以靶向编码密钥的酶/mRNA 有缺陷的代谢途径的步骤，导致有害中间体积累或通过伴侣 治疗以帮助折叠并正确流动突变的蛋白质。基因和等位基因信息越来越多 参与这些目标临床试验的先决条件。在过去的10年中，稀有的肾结石 财团（RKSC）的重点是招募和表征具有单一企业的患者人群 旨在了解疾病的自然史，进行基因型/表型研究以及 将患者分类用于临床研究。这最初涉及桑格测序，但最近涉及 〜100基因面板。作为此次筛查的一部分，假定患者具有原发性高黄油（pH）或 凹陷疾病（两个常见的美元），但Sanger的这些疾病的规范基因中没有突变 测序在面板上筛选。在297名分析患者中，在 30例（10.1％），在11种不同的基因中鉴定出突变。在过去的一年中，所有RKSC招募了患者 采用这种TNGS方法和102个家庭筛选的基本筛查主要是遗传筛查的33 （32.4％）已通过鉴定出8种不同的基因在遗传上解决。有趣的是，在约15％的案件中 在第二个单基因基因中，遗传复杂性与其他可能的致病变异鉴定。 不幸的是，最近损失了RKSC的资金，但我们计划保持财团完好无损，在这里 提议通过RKSC组招募的遗传表征单基金USD，主要是为了识别 患者纳入临床试验。该提案有两个具体的目的：1。具有A的基因型患者 使用全球NGS的肾上石石段或肾球菌病一致的表型 方法和2。表征和分析因病因基因以外的变体阵列 单基石患者。该项目具有共同案例，是USD临床和生化方面的专家 （Lieske博士），也是单基因肾脏疾病遗传学的专家（Harris博士）。测试的TNG 接近的人将与发达而经过验证的生物信息学管道一起使用，以确定可能 因果变体。这些结果将通过咨询和咨询措施返还给推荐医师 变体构象，提供诊断信息，允许个性化治疗，并鼓励临床 试用招募。研究得出的基因变异和变体组合的积累知识 将允许更好地了解这些疾病，并提供对导致遗传因素的见解 表型修饰。

项目成果

New therapeutics for primary hyperoxaluria type 1.

• DOI: 10.1097/mnh.0000000000000790
• 发表时间: 2022-07-01
• 期刊: CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION
• 影响因子: 3.2
• 作者: Dejban, Pegah;Lieske, John C.
• 通讯作者: Lieske, John C.

CYP24A1 deficiency causing persistent hypercalciuria in a stone former.

CYP24A1 缺乏导致结石形成者持续性高钙尿症。

• DOI: 10.1007/s40620-020-00927-6
• 发表时间: 2021
• 期刊: Journal of nephrology
• 影响因子: 3.4
• 作者: Sy-Go,JaninaPaulaT;Zand,Ladan;Harris,PeterC;Lieske,JohnC
• 通讯作者: Lieske,JohnC

Back to the Future: The Role of Metabolic Studies in Therapeutic Advances.

回到未来：代谢研究在治疗进展中的作用。

• DOI: 10.1681/asn.2021101325
• 发表时间: 2021
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Milliner,DawnS;Lieske,JohnC
• 通讯作者: Lieske,JohnC

Kidney Cysts in Hypophosphatemic Rickets With Hypercalciuria: A Case Series.

• DOI: 10.1016/j.xkme.2022.100419
• 发表时间: 2022-03
• 期刊: Kidney medicine
• 影响因子: 3.9
• 作者: Hanna C;Potretzke TA;Chedid M;Rangel LJ;Arroyo J;Zubidat D;Tebben PJ;Cogal AG;Torres VE;Harris PC;Sas DJ;Lieske JC;Milliner DS;Chebib FT
• 通讯作者: Chebib FT

Natural History of Clinical, Laboratory, and Echocardiographic Parameters of a Primary Hyperoxaluria Cohort on Long Term Hemodialysis.

• DOI: 10.3389/fmed.2021.592357
• 发表时间: 2021
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Sas DJ;Enders FT;Gunderson TM;Mehta RA;Olson JB;Seide BM;Banks CJ;Dehmel B;Pellikka PA;Lieske JC;Milliner DS
• 通讯作者: Milliner DS