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

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.

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.

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 COL4A4, MSTO1, FLNA, and APPL1. Of 12 patients with IH, 4 (33%) with painless hematuria had a P/LP variant-1 in each of COL4A3, COL4A5, FLNA, and UQCRC1. Broadening to include the whole exome, no additional P/LP variants believed to be involved in LPHS were identified.

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 (COL4A3-5) were identified in 1 of 17 patients with LPHS and 2 of 12 patients with IH.