Synergistic mutations in SLC3A1 and SLC7A9 leading to heterogeneous cystinuria phenotypes: pitfalls in the diagnostic workup.

BACKGROUND: Cystinuria is an inherited disorder of a renal tubular amino acid transporter and leads to increased cystine excretion with the risk of urinary stone formation. Phenotypical classification is based on urinary amino acid concentration as type I (silent), type non-I (hyper-excretors), mixed or untyped. Genotypic classification is based on mutations in SLC3A1 (type A) or SLC7A9 (type B). CASE-DIAGNOSIS/TREATMENT: We present six family members with a complex phenotypic profile based on mutations in both genes. The index patient presents a known homozygous mutation (p.T189M) in SLC3A1 and a homozygous mutation (c.225C > T) in SLC7A9. Based on a bioinformatics analysis and published findings, we considered p.T189M to be pathogenic and initially classified c.225C > T as a silent variant. However, segregation analysis detected homozygosity for p.T189M also in non-affected individuals, whereas homozygous c.225C > T segregated with the phenotype. RNA studies confirmed c.225C > T to cause aberrant splicing.
CONCLUSIONS: Based on our findings, we conclude that c.225C > T in SLC7A9 determines the clinical phenotype in this family, whereas additional SLC3A1 mutations aggravate the phenotype in heterozygotes for c.225C > T in SLC7A9 without resulting in cystinuria in the homozygous state. Our results underline the need for careful biochemical characterization of family members of an index case of cystinuria. Genetic analysis of both cystinuria genes may be necessary due to the synergistic effects of mutations in two genes.