EXOME SEQUENCING IN PATIENTS WITH LOIN PAIN HEMATURIA SYNDROME AND PERSISTENT ISOLATED HEMATURIA

Loin pain-hematuria syndrome (LPHS) was first described in 1967 and is a rare, complex, and poorly understood painful condition that predominantly affects young women. LPHS severely reduces quality of life. Patients experience debilitating loin pain along with hematuria in the absence of urological or primary kidney pathology. Patients with isolated hematuria without proteinuria or pain have been studied, but our understanding of the etiology of hematuria-associated loin pain remains scarce. Patients with LPHS struggle to achieve pain relief through non-steroidal anti-inflammatory drugs, narcotics, nerve blocks, and surgical intervention. They typically have repeated episodes of gross hematuria, often coinciding with exacerbation of loin pain, but pain can also be chronic and not associated with gross hematuria events. Kidney morphology is normal in these patients, and they typically do not have associated proteinuria or microalbuminuria. In contrast, isolated microscopic hematuria is typically persistent, painless, and does not have proteinuria or microalbuminuria. We hypothesized that exome sequencing could help uncover genetic etiologies in patients with LPHS. In addition to type IV collagen genes (COL4A3, COL4A4, and COL4A5), we expanded our search to focus on other proteins in the Glomerular basement membrane (GBM), endothelium, and podocytes. 

Exome sequencing was performed in 29 consecutive singleton patients: 17 with LPHS and 12 with persistent isolated hematuria without pain. We employed a virtual gene panel approach, focusing on a preselected list of 130 genes linked to hematuria curated from published literature. Bioinformatic analysis, annotation, and interpretation of the variants were performed using the hereditary pipeline of the QIAGEN Clinical Insight (QCI) Interpret Translational (QIAGEN) software and the Franklin platform. Variant pathogenicity was determined by the Franklin pipeline according to the American College of Medical Genetics Association for Molecular Pathology (ACMG/AMP) guidelines. 

Among the 17 patients with LPHS, 13 had gross hematuria and 4 had microscopic hematuria; all had debilitating chronic pain. Nine patients with LPHS had a preceding history of kidney stones, but none had an obstructing stone on imaging at the time of sequencing. Eight patients with LPHS had a family history of kidney stones, 3 had a family history of hematuria, and 2 had a family history of LPHS. Of the 17 patients with LPHS, 5 (29%) had heterozygous pathogenic or likely pathogenic variants in COL4A4, MSTO1, APPL1, CXCR4, and ABCA1 (Table 1).  3 of 12 (25%) patients with isolated painless hematuria had heterozygous pathogenic or likely pathogenic variants in COL4A3, COL4A5, and UQCRC1 (Table 1). 31 variants of uncertain significance (VUS) were identified in 24 hematuria candidate genes. 

LPHS appears to be the result of multiple heterogeneous mechanisms. Our analysis did not identify a single monogenic cause, and rare or multiple variants were observed in different genes among affected individuals. Pathogenic variants in type IV collagen genes (COL4A3, COL4A4, and COL4A5), which are known to cause hematuria, were identified in only 1 of 17 patients with LPHS and 2 of 12 patients with persistent isolated hematuria.