Submission Details

SLC7A9 was first reported in relation to autosomal recessive cystinuria in 1999 (Feliubadaló et al., PMID: 10471498). At least 153 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 12 probands in 5 publications (PMIDs: 23532419, 16609684, 25296721, 11157794, 10471498). Variants in this gene segregated with disease in two additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by the biochemical function of SLC7A9 in a cystine, ornithine, arginine, and lysine transporter protein complex (PMID: 12234930), its interaction with rBAT in that complex (PMID: 18332091), and its expression in the kidneys (PMID: 25613900), where the protein complex absorbs cystine, ornithine, arginine, and lysine back into the blood during urine formation. This gene-disease relationship is further supported by a knockout mouse model which recapitulates the elevated cystine, ornithine, arginine, and lysine levels associated with abnormal function of this protein, leading to formation of cystine crystals and stones in the bladder or kidneys (PMID: 12915471). In mice, as in humans, the heterozygous individuals have an intermediate level of urinary cystine; elevated above normal but lower than the homozygotes (Reviewd in PMID: 30515543). In humans the cystinuria in heterozygotes has, on occassion, been associated with kidney stones however modifying genes or environmental factors may contribute to the phenotype (PMID: 25383320). In summary, SLC7A9 is definitively associated with autosomal recessive cystinuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.