Risk of Nephrolithiasis in adults heterozygous for SLC34A3 Ser192Leu in an unselected health system cohort

Homozygous or compound heterozygous mutations in solute carrier family 34, member 3 (SLC34A3) cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Patients heterozygous for SLC34A3 pathogenic variants may be at increased risk for renal calcification but reports have been mostly limited to family members of patients with autosomal recessive HHRH. To determine the phenotypic spectrum of SLC34A3 Ser192Leu, we examined the most pathogenic SLC34A3 variant Ser192Leu (238 out of 174,417 participants) in an unselected, health system-based research cohort in central and northeast Pennsylvania. SLC34A3 Ser192Leu heterozygotes had higher risks of nephrolithiasis ICD diagnosis (13% vs. 6%), hypophosphatemia <2.5 mg/dL (31/96 [32%] vs. 6226/39636 [16%]), lower eGFR (-4.43, 95% CI: -7.03, -1.83; p=0.001) and tended to have higher prevalence of kidney/liver cyst ICD codes (5% vs. 3%; p=0.09), compared to controls. Further studies are needed to determine whether personalized approaches (i.e. phosphate supplementation) to patients heterozygous for SLC34A3 pathogenic variants can reduce kidney stone burden and risk of kidney function decline.