Login to Access Video or Poster Abstract: MP12-11
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Introduction

Cystine stones are caused by cystinuria, an inborn error of metabolism. The pathogenesis of cystine stones and cystinuria have been re-classified by genetic mutations. It is defined as type A if mutations are found in both SLC3A1 alleles, and type B if mutations are found in both SLC7A9 alleles. However, the prevalence of type A and type B cystine stones has not been evaluated. We aim to clarify the prevalence of type A and type B cystine stones by employing a genetic approach.

Methods

We have accessed the 1000 Genomes Database Phase 3 (1KG) for identification of variants in the general population. To identify pathogenic mutations, we parsed the Human Gene Mutation Database (HGMD)._x000D_ _x000D_ SLC3A1 and SLC7A9 variants procured from both databases were intersected. Homozygotes, compound heterozygotes, multiple variants in cis or trans, double homozygotes, and double heterozygotes were examined. Related individuals were excluded. Pathogenic allele frequency, carrier rate and affected rate were calculated and estimated based on Hardy-Weinberg equilibrium.

Results

In 1KG, non-related healthy individuals (n=2504) carry SLC3A1 and SLC7A9 variants in 1705 and 1287 loci, respectively. In HGMD, there are 110 pathogenic SLC3A1 mutations, and 85 for SLC7A9. These variants include missense mutations, nonsense mutations, insertions, deletions, and complex substitutions._x000D_ _x000D_ Among 2504 non-related, healthy individuals in 1KG, there are 26 people who carry 9 different SLC3A1 mutations, while 12 people carry 5 different SLC7A9 mutations. There were no homozygotes, compound heterozygotes, multiple variants in cis or trans, double homozygotes, or double heterozygotes._x000D_ _x000D_ Therefore, disease-causing alleles have a frequency of 0.52% for SLC3A1, and 0.24% for SLC7A9._x000D_ Type A cysteine stone has a carrier rate of 1 in 96 individuals and affected rate of 1 in 37,100 individuals._x000D_ For type B, carrier and affected rates would be 1 in 209 and 1 in 174,167, respectively. _x000D_ The combined (type A + type B) carrier rate for cysteine stones is 1 in 66, with an overall affected rate of 1 in 30,585. _x000D_ _x000D_

Conclusions

The prevalence of cystine stone type A and type B estimated from a genetic approach is lower than the prevalence of observed of phenotypes (1 in 30,585 v.s. 1 in 7,000). Possible explanations include undiscovered mutations, undiscovered genes, a different inheritance model, selection advantages over the pathogenic variant, or founder effect. Further studies and investigations are required.

Funding

none