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

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.

Presentation and Variability of APOL1-Related Kidney Disease

Inheritance of the APOL1 G1 or G2 risk alleles in the homozygous or compound heterozygous state, are associated with a ~7-30X increased risk of development of chronic kidney disease (CKD), and with collapsing glomerulopathies in individuals with viral infections including COVID-19 or HIV. Identification of APOL1 high risk genotypes (HRG) can impact patient treatment, prognosis and kidney donor selection. Approximately 13% of African Americans (AA) have an APOL1 HRG, indicating genetic testing in this population can identify those at-risk for CKD development, leading to appropriate patient counseling and management. Here we sought to understand the clinical presentation and variability among patients with APOL1 HRGs, following the implementation of genetic testing for kidney disease with a broad panel at a Louisiana Nephrology clinic. Clinical genetic testing of patient samples was performed using a >380 kidney gene panel (the RenasightTM test, Natera, Inc.) A retrospective review of clinical data for individuals positive for an APOL1 HRG (G1/G1, G2/G2, G1/G2) was performed. We identified 12 patients that were positive for an APOL1 HRG, with all genotypes represented: G1/G1 (n=8), G1/G2 (n=3), and G2/G2 (n=1). Among this cohort, 100% (12/12) were of AA descent. At the time of testing 91% (11/12) of the patients were diagnosed with CKD or ESRD with proteinuria. Biopsy confirmed focal segmental glomerulosclerosis (FSGS) in two patients and collapsing glomerulopathy in one patient. The most common comorbidities among this cohort were hypertension (9/12) and diabetes mellitus (2/12). Four patients had a history of infection with COVID-19 (n=3) or HIV (n=1), three of whom had renal involvement (acute kidney injury or CKD and proteinuria). Use of a broad kidney gene panel enabled the identification of APOL1 HRGs in individuals for which hypertension or diabetes may have otherwise been attributed as the primary cause of CKD. APOL1 HRGs could also provide context for the renal involvement seen in the patients with COVID-19 or HIV infection. Broad panel genetic testing provides an accessible tool for nephrology clinics to help identify individuals at risk for positivity for an APOL1 HRG, including those of AA descent with hypertensive, proteinuric CKD.