New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype

Objective: To clarify the genotype - phenotype correlation and elucidate the role of digenic inheritance in cystinuria. Methods: 164 probands from the International Cystinuria Consortium were screened for mutations in SLC3A1 ( type A) and SLC7A9 ( type B) and classified on the basis of urine excretion of cystine and dibasic amino acids by obligate heterozygotes into 37 type I ( silent heterozygotes), 46 type non- I ( hyperexcretor heterozygotes), 14 mixed, and 67 untyped probands. Results: Mutations were identified in 97% of the probands, representing 282 alleles ( 86.8%). Forty new mutations were identified: 24 in SLC3A1 and 16 in SLC7A9. Type A heterozygotes showed phenotype I, but mutation DupE5- E9 showed phenotype non- I in some heterozygotes. Type B heterozygotes showed phenotype non- I, with the exception of 10 type B mutations which showed phenotype I in some heterozygotes. Thus most type I probands carried type A mutations and all type non- I probands carried type B mutations. Types B and A mutations contributed to mixed type, BB being the most representative genotype. Two mixed cystinuria families transmitted mutations in both genes: double compound heterozygotes ( type AB) had greater aminoaciduria than single heterozygotes in their family. Conclusions: Digenic inheritance is an exception ( two of 164 families), with a limited contribution to the aminoaciduria values ( partial phenotype) in cystinuria. Further mutational analysis could focus on one of the two genes ( SLC3A1 preferentially for type I and SLC7A9 for type non- I probands), while for mixed probands analysis of both genes might be required, with priority given to SLC7A9.