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

Chuangye Li,Yongjia Yang,Yu Zheng,Li Liu,Fang Shen,Liping Li,Yanfang Li,Yaowang Zhao

doi:10.3389/fgene.2020.00074

Chuangye Li, Yongjia Yang + Show 6 more

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https://doi.org/10.3389/fgene.2020.00074

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Abstract

BackgroundCystinuria 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.MethodUrinary 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.ResultsFrom 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 cm3 to 18.67 cm3. 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.ConclusionAll 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.

Highlights

Cystinuria is a rare genetic disorder characterized by defective renal reabsorption of cystine, ornithine, arginine, and lysine
A total of 24 pathogenic variants in SLC3A1 and SLC7A9 were detected, 15 of which were novel. These data expanded the spectrum of cystine urolithiasis (CU) variants in the Chinese population
A total of 13 patients with CU were identified, 10 of whom were males and 3 were females. These patients originated from 232 patients with urinary stones that we treated from 2002 to 2007

Summary

Introduction

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). Most kidney stones form because of a combination of genetics and environmental factors (Miller and Lingeman, 2007). Cystine urolithiasis (CU) is a genetic disorder characterized by defective renal reabsorption of cystine, arginine, lysine, and ornithine; the increased urinary excretion of cystine results in the formation of kidney stones (Eggermann et al, 2012; Fattah et al, 2014). The inheritance for cystinuria may vary from autosomal recessive (AR) to autosomal dominant (AD) with incomplete penetrance to digenic pattern (Dello Strologo et al, 2002; Sahota et al, 2019). Cystinuria is divided into the following subtypes: biallelic SLC3A1 mutations (AA genotype), biallelic SLC7A9 mutations (BB genotype), a single heterozygous SLC3A1 mutation (A genotype), a single heterozygous SLC7A9 mutation (B genotype), and a single heterozygous SLC3A1 mutation combined with a single heterozygous SLC7A9 mutation (AB genotype) (Dello Strologo et al, 2002; Sahota et al, 2019)

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