The role of double heterozygotes of SLC3A1 and SLC7A9 in the prevalence of cystine stones

Abstract

PurposeCystine stones, an autosomal recessive disorder caused by cystinuria, result from pathogenic variants of SLC3A1 and SLC7A9. Previous publications revealed that clinical prevalence is higher than genetically predicted prevalence. Heterozygous carriers in either gene are not stone formers. However, double heterozygotes (DH), individuals with 2 heterozygous pathogenic variants in both genes, were never evaluated and may explain the gap between clinical and genetic prevalence. MethodsBecause of the rarity of the condition, direct clinical observation is impractical. We perform this population study as a surrogate by identifying the observed DH, deriving the theoretical/expected DH, and testing the null hypothesis (NH) that the observed DH frequency is equal or greater than expected. These NH biologically correlate to DH and are asymptomatic and without cystine stone. ResultsUsing the 1000 Genome Database, we identified 0 DH. We derived the theoretical/expected DH with Hardy-Weinberg Equilibrium and Mendel’s law of independent assortment as 4.94 × 10−s. Population proportion test revealed z = −0.353, and P = .362, the NH cannot be rejected. ConclusionStatistical testing does not support that DH are symptomatic, ie, DH of SLC3A1 and SLC7A9 may not present with cystine stone, and other factors responsible for the gap that current genetics knowledge cannot explain.