Impact of Genetic Testing in Nephrology: A Family's Experience with Dent Disease 2

ABSTRACT

Diagnosis of a genetic kidney disease can enhance treatment/management, allow patient/family counseling, and enable patient referral to specialists or clinical trials. Here we present a case study describing the use of a >380 gene panel associated with kidney diseases (The RenasightTM test, Natera, Inc.) to diagnose Dent disease 2 in a patient and their family members. A 41-year-old male was referred to Nephrology for evaluation of elevated SCr (4.6 mg/dL) and proteinuria. The patient’s medical history was unremarkable except for glaucoma in infancy. A renal biopsy identified glomerulomegaly. Genetic testing identified a likely pathogenic, hemizygous, frame-shift variant (c.311del;p.Cys104Phefs*2) in exon 5 of OCRL, an X-linked gene, which is associated with Dent disease 2. This genetic diagnosis prompted changes to the patient’s treatment plan, including patient counseling and preparation for renal replacement therapy (RRT). The patient’s 46-year-old brother was hospitalized due to COVID-19 symptoms with a SCr of 19.1 mg/dL. Due to limited medical history, it was unclear if he was presenting with acute kidney injury or chronic kidney disease. Although there was no evidence of nephrolithiasis or renal tubular acidosis typically associated with Dent disease 2, the family history prompted genetic testing that confirmed the presence of the familial variant in this patient. These genetic findings prevented delay in treatment, namely, initiation of RRT. Given the X-linked inheritance of Dent disease 2, the patients’ mother is an obligate carrier of the p.Cys104Phefs*2 variant in OCRL. Therefore, the third brother is an appropriate candidate for genetic testing due to his 50% chance of inheriting the familial variant. In this family, identification of an OCRL variant via broad panel renal genetic testing impacted patient counseling, management, and family testing. Notably, without genetic testing for the proband, his brother’s condition may have gone undiagnosed due to the atypical presentation, demonstrating the variability of OCRL-related conditions. Genetic testing can enable accurate disease diagnosis in individuals with an atypical presentation, syndromic kidney disease and/or a family history.