Thaxton Courtney, Goldstein Jennifer, DiStefano Marina, Wallace Kathleen, Witmer P Dane, Haendel Melissa A, Hamosh Ada, Rehm Heidi L, Berg Jonathan S
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Lead contact.
Cell Genom. 2022 May 11;2(5). doi: 10.1016/j.xgen.2022.100131.
The dilemma of how to categorize and classify diseases has been debated for centuries. The field of medical genetics has historically approached nosology based on clinical phenotypes observed in patients and families. Advances in genomic sequencing and understanding of genetic contributions to disease often provoke a need to reassess these classifications. The Clinical Genome Resource (ClinGen) has developed frameworks to classify the strength of evidence underlying monogenic gene-disease relationships, variant pathogenicity, and clinical actionability. It is therefore necessary to define the disease entity being evaluated, which can be challenging for genes associated with multiple conditions and/or a broad phenotypic spectrum. We therefore developed criteria to guide "lumping and splitting" decisions and improve consistency in defining monogenic gene-disease relationships. Here, we outline the precuration process, the lumping and splitting guidelines with examples, and describe the implications for clinical diagnosis, informatics, and care management.
如何对疾病进行分类的难题已经争论了几个世纪。医学遗传学领域历来是根据在患者及其家族中观察到的临床表型来进行疾病分类学研究的。基因组测序技术的进步以及对疾病遗传因素的深入理解，常常引发重新评估这些分类的需求。临床基因组资源库（ClinGen）已经制定了一些框架，用于对单基因基因-疾病关系、变异致病性以及临床可操作性的证据强度进行分类。因此，有必要明确所评估的疾病实体，这对于与多种病症和/或广泛表型谱相关的基因来说可能具有挑战性。为此，我们制定了一些标准来指导“合并与拆分”决策，并提高在定义单基因基因-疾病关系时的一致性。在此，我们概述了预筛选过程、带有示例的合并与拆分指南，并描述了对临床诊断、信息学和护理管理的影响。
