Cystine stones are caused by pathogenic variants in SLC3A1 or SLC7A9. Our prior study revealed a large gap between genetic and clinical prevalence. With increasing discovery of novel variants, we aim to assess how these impact genetic prevalence estimates. Due to the disease rarity, direct patient recruitment and observation is impractical. We applied a population genetics approach to estimate genetic burden and prevalence. Pathogenic variants were identified from the 2022 Human Gene Mutation Database and intersected with population variants from the 1000 Genomes Project Phase 3. Allele frequency, carrier rate, and affected rate were calculated. Results were compared to prior data, and simulations were performed across varying initial allele frequencies. We identified 116 and 76 novel pathogenic variants in SLC3A1 and SLC7A9, respectively. Pathogenic allele frequencies increased by +0.12% (SLC3A1) and 0.16% (SLC7A9), leading to fold-changes in genetic prevalence of 1.51x and 2.78x. The combined updated prevalence is 1 in 17,612, a 1.74x increase. Simulations confirmed the fold-change magnitude. In rare diseases, even modest discovery of new variants can significantly increase genetic prevalence. As shown in cystine stone, this helps narrow-but not close-the gap with clinical prevalence. Further efforts are needed to bridge this gap and guide treatment development.
European journal of human genetics : EJHG. 2026 Apr 09 [Epub ahead of print]
Chen-Han Wilfred Wu, Joshua Chang, Katreya Lovrenert, Donald Bodner, Friedhelm Hildebrandt, Fredrick R Schumacher
Department of Urology, Department of Genetics, Hugh Kaul Precision Medicine Institute Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. ., Department of Urology, Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA., Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA., Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.