Granhøj Jeff, Pedersen Katja Venborg, Aagaard Mads Malik, Graakjaer Jesper Aagaard, Lildballe Dorte Launholt, Birn Henrik, Rasmussen Maria
Department of Clinical Genetics, Lillebaelt Hospital-University Hospital of Southern Denmark, Vejle, Denmark.
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
Clin Kidney J. 2024 Jun 11;17(7):sfae166. doi: 10.1093/ckj/sfae166. eCollection 2024 Jul.
Genomic disorders caused by copy number variations (CNVs) are prevalent in patients with kidney disease; however, their contribution to chronic kidney failure (KF) of undetermined aetiology (uKF) is unclear. We screened patients with uKF aged 50 years or younger to establish the prevalence of causative CNVs.
We enrolled patients with an onset of KF ≤50 years from suspected undetermined aetiology for initial review of medical records to exclude patients with clear-cut clinical or histopathological kidney diagnoses or patients with already established genetic kidney diseases. Next, we performed single nucleotide polymorphism (SNP) array-based CNV screening. All the detected CNVs were systematically classified and evaluated as possible causes of the patient's kidney disease. Patients with CNVs not explaining the kidney phenotype were additionally screened for causal variants in 540 genes using whole-genome sequencing.
We enrolled 172 patients, of whom 123 underwent SNP-array. Pathogenic CNVs corresponding to known genomic disorders were identified in 12 patients (9.8%). The identified genomic disorders provided a causative kidney diagnosis in three patients, all of whom had reached KF by age 18 years. The remaining nine patients had CNVs with unclear kidney disease causality. Subsequently, whole-genome sequencing provided a causative genetic diagnosis in an additional four patients, including two diagnostic sequence variants unrelated to the detected CNVs.
Genomic disorders were prevalent in this cohort with uKF, and causative CNVs were identified in 5 of 123 patients. Further studies combining the analysis of CNVs and sequence variants are needed to clarify the causal role of genomic disorders in kidney disease.
由拷贝数变异（CNV）引起的基因组疾病在肾病患者中很常见；然而，它们对病因不明的慢性肾衰竭（KF）的影响尚不清楚。我们对50岁及以下的病因不明的KF患者进行筛查，以确定致病性CNV的患病率。
我们纳入了KF发病年龄≤50岁、病因疑似不明的患者，对其病历进行初步审查，以排除具有明确临床或组织病理学肾脏诊断的患者或已确诊的遗传性肾脏疾病患者。接下来，我们进行了基于单核苷酸多态性（SNP）阵列的CNV筛查。所有检测到的CNV都被系统地分类和评估，作为患者肾脏疾病的可能病因。对于CNV不能解释肾脏表型的患者，我们使用全基因组测序对540个基因中的因果变异进行了额外筛查。
我们纳入了172例患者，其中123例接受了SNP阵列检测。在12例患者（9.8%）中鉴定出与已知基因组疾病相对应的致病性CNV。鉴定出的基因组疾病为3例患者提供了病因性肾脏诊断，所有这些患者在18岁时均已发展为KF。其余9例患者的CNV与肾脏疾病因果关系不明确。随后，全基因组测序又为另外4例患者提供了病因性基因诊断，其中包括2个与检测到的CNV无关的诊断性序列变异。
在这个病因不明的KF队列中，基因组疾病很常见，在123例患者中有5例鉴定出了致病性CNV。需要进一步结合CNV和序列变异分析的研究，以阐明基因组疾病在肾脏疾病中的因果作用。
