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

[cystinuria]

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 SLC 3 A 1 (type A ) or SLC 7 A 9 (type B ).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 .T 189 M ) in SLC 3 A 1 and a homozygous mutation (c .225 C > T ) in SLC 7 A 9 . Based on a bioinformatics analysis and published findings , we considered p .T 189 M to be pathogenic and initially classified c .225 C > T as a silent variant . However , segregation analysis detected homozygosity for p .T 189 M also in non-affected individuals , whereas homozygous c .225 C > T segregated with the phenotype . RNA studies confirmed c .225 C > T to cause aberrant splicing .Based on our findings , we conclude that c .225 C > T in SLC 7 A 9 determines the clinical phenotype in this family , whereas additional SLC 3 A 1 mutations aggravate the phenotype in heterozygotes for c .225 C > T in SLC 7 A 9 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 .