Genetic and Clinical Analyses of 13 Chinese Families With Cystine Urolithiasis and Identification of 15 Novel Pathogenic Variants in SLC3A1 and SLC7A9

Abstract

Background: Cystinuria is a rare genetic disorder characterized by defective renal reabsorption of cystine, ornithine, arginine, and lysine. The increased urinary excretion of cystine results in the development of cystine urolithiasis (CU). The mutated SLC3A1 and SLC7A9 genes are the cause of CU, a global disorder. Its frequency and mutation spectrum vary between different populations. In Asia, the data for CU are limited.Method: Urinary stones were collected from patients of a single center over a five-year period and analyzed via Fourier transform infrared spectroscopy. Genomic DNA was isolated from 13 patients with CU and their parents and from 26 controls affected by calcium oxalate dihydrate stones. The coding regions and the exon-intron boundaries of SLC3A1 and SLC7A9 were subjected to PCR amplification and then sequenced via traditional Sanger sequencing. Genetic variants were functionally annotated using the InterVar, ClinVar, gnom AD, and HGMD databases.Results: From the 232 samples of urinary stones, we identified 13 patients with CU (10 males and 3 females). The onset age was from 7 months to 9 years. The CU stones varied from 0.26 cm 3 to 18.67 cm 3 . Sanger sequencing detected a total of 14 SLC3A1 (nine were novel) and 10 SLC7A9 (six were novel) rare variants from the 13 CU families. All variants, including 15 novel variants, were pathogenic, disease-causing, or damaging.Conclusion: All 13 pediatric CU families harbored SLC3A1 or/and SLC7A9 rare variants. A total of 15 novel pathogenic variants in SLC3A1 and SLC7A9 were identified. This study expanded the known mutational spectrum of CU in the Chinese population.

Clinical Characteristics and In Silico Analysis of Cystinuria Caused by a Novel SLC3A1 Mutation

“…By using the WES approach, a double heterozygous variant in the gene SLC3A1 (NM_000341.4: c. 818G>A, p. Cys273Tyr; c. 1011 G>A, p. Pro337Pro) was identified, of which c. 818.G>A was a novel variant. A 9-year-old male patient who suffered from nine operations to remove a cystine stone was reported to have a heterozygous mutation (c.817T>C and c.1097A>G) located at the Cys273 and Gln366 site of SLC3A1, respectively [ 17 ]. Two cystinuria cases with c. 1011G>A from Quebec and France have been reported previously [ 29 , 30 ].…”

“…Cystinuria can be categorized into three types: SLC3A1 mutation is known as type A; SLC7A9 mutation is known as type B; both SLC3A1 and SLC7A9 mutations are known as type AB [ 15 ]. To date, a total of 210 clinical mutations of SLC3A1 have been documented by the Human Gene Mutation Database (HGMD), and genetic diversity of the population has been reported in different ethnic groups [ 16 , 17 , 18 ], indicating substantial heterogeneity in the genetic basis of cystinuria. A landscape of the genetic mutations related to cystinuria would contribute to the progression of gene therapy for abnormal cystine sedimentation.…”

Declaration: Novel SLC3A1 mutation in a cystinuria patient with xanthine stones: a case report

“…Genetic testing by next-generation sequencing (NGS) carried out with the patient’s informed consent revealed a homozygous nonsense mutation (c.1113C> A, p.Tyr371*) in the SLC3A1 gene. There are multiple reports of nonsense variants causing disease in the upstream and downstream of this variant [ 8 , 9 ], thus implicating loss-of-function as one of the pathogenic mechanisms of the disease. Four cases of heterozygotes of this variant are reported in the gnomAD population database, while no homozygous individuals have been found.…”