The Role of Double Heterozygotes of SLC3A1 and SLC7A9 in the Prevalence of Cystine Stones.

Purpose: Cystine stones, an autosomal recessive disorder caused by cystinuria, result from pathogenic variants of SLC3A1 and SLC7A9. Previous publications revealed clinical prevalence is higher than genetically predicted prevalence. Heterozygous carriers in either gene are not stone formers. However, double heterozygotes (DH), individuals with two heterozygous pathogenic variants in both genes, were never evaluated and may explain the gap between clinical and genetic prevalence.
Methods: Due to 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. This NH biologically correlates to DH are asymptomatic and without cystine stone.
Results: Using 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 4.94x10-s. Population proportion test revealed Z= -0.353, and p= 0.362, the NH cannot be rejected.
Conclusion: Statistical testing does not support that DH are symptomatic, i.e. DH of SLC3A1 and SLC7A9 may not present with cystine stone, and other factors responsible for the gap that current genetics knowledge cannot explain.
(Copyright © 2024. Published by Elsevier Inc.)