Exome sequencing yields genetic diagnoses among patients with chronic kidney disease

1. Proband exome sequencing revealed that approximately 10% of patients in this study cohort had a detectable genetic variant of chronic kidney disease.

2. A majority of the monogenic disorders that were detected were found to be unique to individual patients.

Evidence Rating Level: 2 (Good)

Study Rundown: Exome sequencing is a diagnostic tool that is increasingly being used to detect various cancer mutations and origins of metabolic disease, however its use to detect genetic origins of constitutional disease has remained limited. In this current analysis, researchers used exome sequencing to evaluate possible genetic origins of chronic kidney disease among 3315 patients enrolled in two other research studies, A Study to Evaluate Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) and from the Columbia University Medical Center (CUMC) Genetic Studies of Chronic Kidney Disease cohorts. Overall, approximately 9.3% of patients had detectable diagnostic variants of chronic kidney disease. Many of these genetic diagnoses encompasses unique, patient specific monogenetic disorders. Researchers were also able to pinpoint clinical findings to specific gene mutations, allowing for disease reclassification and additional clinical insight.

These results highlight the potential genome sequencing has to guide clinical decision making and offer targeted therapies. Strengths of the study include the large sample size, diversity of the patient population studies, and generalizability of studying patients with a clinical diagnosis. Limitations include those inherent to exome sequencing, such as imperfect genome coverage, and absent discussion of cost-benefit considerations for such prospective widespread genetic evaluation of this clinically diagnosed disease.

Click to read the study in NEJM

Relevant Reading: Whole-exome sequencing in adults with chronic kidney disease: a pilot study

In-Depth [retrospective cohort]: This analysis performed exome sequencing on 3315 patients enrolled in two study cohorts; 1128 patients from AURORA and 2187 patients from the CUMC Genetic Studies of Chronic Kidney Disease. All patients were clinically diagnosed with chronic kidney disease. Clinically, all patients had some degree of nephropathy and 2144 of 3315 patients (64.7%) had end-stage renal disease (all 1128 patients in the AURORA cohort and 1016 (46.5%) of the CUMC cohort). There were 66 distinct diagnostic genetic variants of nephropathy found in 307 of the 3315 patients (9.3%). Autosomal dominant disease was present in 67% (206/307) of patients with a genetic variant. Of these 66 distinct disorders, 59% (39 of 66) were unique disorders that were specific to individual patients, while 6 diagnoses represented 198 (63%) of all the genetic diagnosis. Researchers also used data from the CUMC cohort to study diagnostic utility and clinical implications of genetic findings. Among the 167 patients in the CUMC cohort with genetic-derived disease, 122 patients (73%) had data that allowed for new clinical insight into their conditions. For example, researchers were able to pinpoint a specific genetic focus for a patient’s cystic disease or nephropathy of unknown origin, which allowed for disease reclassification.

Image: PD

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