Population Genetics Analysis ofSLC3A1andSLC7A9Revealed the Etiology of Cystine Stone May Be More Than What Our Current Genetic Knowledge Can Explain

Abstract

AbstractBackgroundCystine stone is a Mendelian genetic disease caused bySLC3A1orSLC7A9. In this study, we aimed to estimate the genetic prevalence of cystine stones and compare it with the clinical prevalence to better understand the disease etiology.MethodsWe analyzed genetic variants in the general population using the 1000 Genomes project and the Human Gene Mutation Database to extract allSLC3A1andSLC7A9pathogenic variants. All variants procured from both databases were intersected. Pathogenic allele frequency, carrier rate, and affected rate were calculated and estimated based on Hardy-Weinberg equilibrium.ResultsWe found that 9 uniqueSLC3A1pathogenic variants were carried by 26 people and 5 uniqueSLC7A9pathogenic variants were carried by 12 people, all of whom were heterozygote carriers. No homozygote, compound heterozygote, or double heterozygote was identified in the 1000 Genome database. Based on the Hardy-Weinberg equilibrium, the calculated genetic prevalence of cystine stone disease is 1 in 30,585.ConclusionThe clinical prevalence of cystine stone has been previously reported as 1 in 7,000, a notably higher figure than the genetic prevalence of 1 in 30,585 calculated in this study. This suggests that the etiology of cystine stone is more complex than what our current genetic knowledge can explain. Possible factors that may contribute to this difference include novel causal genes, undiscovered pathogenic variants, alternative inheritance models, founder effects, epigenetic modifications, environmental factors, or other modifying factors. Further investigation is needed to fully understand the etiology of cystine stone.