Cystinuria in clinical practice: challenges in genetic verification and laboratory diagnosis

Cystinuria is an inherited disorder caused by impaired reabsorption of cystine and dibasic amino acids—ornithine, lysine, and arginine—in the proximal renal tubules. Ornithine, arginine, and lysine are highly soluble in urine, but the solubility of cystine depends on pH and is low under physiological conditions. The genetic basis of cystinuria involves mutations in the SLC3A1 gene (encoding the heavy subunit rBAT of the Na⁺-independent amino acid transporter (rBAT-b^0,+AT) and the SLC7A9 gene (encoding the light subunit b^0,+AT). Dysfunction of the rBAT-b^0,+AT transporter leads to excessive cystine excretion, promoting urine supersaturation, crystallization, and the formation of cystine stones. Mutations in SLC7A9 exhibit a broad inheritance spectrum, ranging from recessive to dominant. Mutations in SLC3A1 are usually considered autosomal recessive; heterozygous carriers of these mutations mostly have a normal urinary amino acid profile, whereas homozygotes exhibit various symptoms of cystinuria. Accumulating clinical evidence reveals genotypic–phenotypic discordance that challenges this classical model. This review systematizes atypical cases where heterozygous carriers of pathogenic SLC3A1 mutations manifest recurrent cystine stones and hypercystinuria, whereas family members with identical mutations remain asymptomatic. Notably, approximately 10% of patients lack detectable mutations in the coding regions of these genes, suggesting the potential involvement of non-coding regulatory regions or modifier genes, including but not limited to SLC7A10 (ASC1), SLC1A5 (ASCT2), and SLC7A13 (AGT1). The review concludes that additional methods, such as whole-genome sequencing of well-characterized families, are necessary to identify these hidden genetic factors, improve diagnostic accuracy, and better understand the molecular mechanisms underlying cystinuria.