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Abstract: SA-PO582

Prevalence and Phenotypic Spectrum of Heterozygous SLC34A3 Mutations in a Large Genetic Database

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Nwachukwu, Chinedu O., Geisinger Medical Center, Danville, Pennsylvania, United States
  • Singh, Gurmukteshwar, Geisinger Medical Center, Danville, Pennsylvania, United States
  • Moore, Bryn S., Geisinger Medical Center, Danville, Pennsylvania, United States
  • Strande, Natasha T., Geisinger Medical Center, Danville, Pennsylvania, United States
  • Bucaloiu, Ion D., Geisinger Medical Center, Danville, Pennsylvania, United States
  • Chang, Alex R., Geisinger Medical Center, Danville, Pennsylvania, United States
Background

Homozygous or compound heterozygous mutations in SLC34A3, encoding the sodium dependent inorganic phosphate cotransport proteins 2c (NPT2c), cause autosomal recessive hypophosphatemic rickets with hypercalciuria. Whether heterozygous carriers of SLC34A3 pathogenic variants have increased risk of nephrolithiasis or other renal disorders is unknown.

Methods

We included participants heterozygous for SLC34A3 S192L in the Geisinger MyCode/DiscovEHR study, an unselected health-system-based study with exome sequencing data linked to electronic health records (EHR). We reviewed EHR for nephrolithiasis-related labs, diagnoses in progress notes or imaging, workup, nephrology and urology encounters.

Results

Of 174,418 MyCode participants, 238 (0.14%) were heterozygous for SLC34A3 S192L. We excluded 3 with SLC34A3 variants of uncertain significance and those without EHR data. Of the 217 remaining (mean age 58.6 years, 63% female), 65 (30%) had evidence of nephrolithiasis, including 13 who had incidental nephrolithiasis on imaging, and 2 had nephrocalcinosis. Only 21/65 with nephrolithiasis had urology visits for nephrolithiasis (15 had urologic procedures) and 13/65 were seen by nephrology for nephrolithiasis. Only 11 (5.5%) participants had family history of nephrolithiasis noted. Nephrolithiasis lab tests were rarely done. Of 88 participants with available serum phosphorus, 34 (39%) had hypophosphatemia <2.5 mg/dL at least once. Among 9 patients who had a completed 24-hour urine risk profile, mean 24-hour urine calcium was 294 mg/d (67% >250 mg/d), mean 24-hour urine phosphorus was 856 mg/d (33% > 1100 mg/d). Kidney stone analysis on 3 patients indicated calcium oxalate stone composition. Prescriptions potentially increasing nephrolithiasis risk included calcium supplements in 12 (6%) and vitamin D supplements in 29 (13%). No participants were taking phosphate supplements.

Conclusion

In our unselected EHR-based cohort, approximately 1/3 of SLC34A3 S192L heterozygotes had evidence of nephrolithiasis. Few were comprehensively evaluated for nephrolithiasis, and many were taking potentially contraindicated medications. Further studies will help determine if personalized management could improve nephrolithiasis risk in this population.