Exome Sequencing in Patients with Loin Pain Hematuria Syndrome and Persistent Isolated Hematuria.

Introduction: Loin pain hematuria syndrome (LPHS) is characterized by chronic loin pain and hematuria without a urological cause. We hypothesized that rare genetic variants in genes impacting the glomerular filtration barrier (endothelial cells, glomerular basement membrane, or podocytes) may contribute to LPHS. Methods: Exome sequencing was performed in 29 consecutive patients; 17 with LPHS, and 12 with persistent painless isolated hematuria (IH). We first evaluated a virtual gene panel of 130 hematuria-linked genes curated from the literature followed by an exome-wide analysis. Variant interpretation was performed using clinical criteria. Results: Of 17 patients with LPHS, 13 had gross hematuria, 4 had microscopic hematuria, all with chronic pain. Of these, 9 had a history of kidney stones, but none had obstruction on current imaging; 8 had a family history of kidney stones, 3 of hematuria, and 2 of LPHS. Of 17 patients with LPHS, 4 (23%) had a heterozygous pathogenic or likely pathogenic (P/LP) variant-1 in each of Conclusions: LPHS appears to be the result of multiple heterogeneous mechanisms. Our analysis did not identify a common monogenic cause, but rare variants were observed in multiple genes among affected individuals. Pathogenic variants in type IV collagen genes (