Role of Family History and Genetic Testing in Diagnosing Rare Diseases

Introduction: Fibronectin nephropathy (FN) is an autosomal dominant disease characterized by proteinuria, hematuria, and decline in kidney function [1]. The diagnosis is made with kidney biopsy (KB) showing fibrillary mesangial and subendothelial deposits immunoreactive to fibronectin [1, 2]. There is no treatment and there is a risk of recurrence after transplant [3]. We present two cases of FN that reinforce the need for dedicated family history (FH) and genetic analyses. Case Description: A 44-year-old female presented for evaluation of proteinuria. Her mother had membranoproliferative glomerulonephritis (MPGN) at age 45, and later ESKD requiring transplant. Physical exam was benign. Urine protein creatinine ratio (UPCR) was 1.26 gm/gm, hepatitis panel, ANA, C3, C4 and kidney ultrasound were normal. Image 1 is the patient’s KB results; however, there was insufficient sample, and it did not reveal a diagnosis. Due to the FH of MPGN and to help with her diagnosis, the patient allowed a re-analysis of her deceased mother’s KB. There were many similarities between the KBs. A genetic test for the mutation W1925R in the FN1 gene was positive, leading to diagnosis of FN for her, and likely for her mother [4]. She is now on lisinopril, with recent UPCR .65 gm/gm. Discussion: FN is diagnosed with KB. This patient was unique since she did not have classic findings on KB, but her mother had MPGN and later ESKD. The FH prevented a second KB, and instead received a diagnosis from a genetic test. This case demonstrates the vital role of FH and the benefit of having a multi-disciplinary team, specifically nephrologist, renal pathologist, and genetic counselor.Patient (1, 2) and mother KB (3, 4) shows large amounts of subendothelial and mesangial electron-dense deposits with vague fibrillary structure under high-power magnification. The mother's KB was post-transplant with recurrent disease.