Two novel heterozygous ADCY10 variants identified in Chinese pediatric patients with absorptive hypercalciuria: case report and literature review.

Absorptive hypercalciuria (AH) is a prevalent cause of kidney stones, and the adenylate cyclase 10 (ADCY10) gene is a rare causative gene of AH. This study aims to investigate the genotypic and phenotypic characteristics of patients with AH caused by ADCY10 gene mutations. Whole-exome sequencing and Sanger sequencing were performed on the probands and their family members, respectively. Clinical and genetic data of patients with AH caused by ADCY10 gene mutations were collected and analysed retrospectively from the present study and published literature. Two female patients (6 years old and 1 year old) with multiple bilateral kidney stones were found to have a heterozygous c.3304T>C mutation and a heterozygous c.1726C>T mutation in the ADCY10 gene. Urinary metabolite analysis revealed that urine calcium / creatinine ratios were 0.95 mmol/mmol and 1.61 mmol/mmol, respectively. Both patients underwent thiazide intake postoperatively, and upon reexamination, urine calcium decreased to within the normal range. A total of 61 patients with AH were reported from previous and present studies. The sex ratio was 7:5 for males to females, and the mean age of onset was 23.61±20.08 years. A total of 16 ADCY10 gene mutations were identified, including seven missense (43.75%), five splicing (31.25%), two frameshift (12.50%) and two nonsense mutations (12.50%). Only two cases were identified as homozygous mutations (c.1205_1206del), and the others were heterozygous mutations. In summary, we identified two novel ADCY10 gene candidate pathogenic variants in Chinese pediatric patients, which expands the mutational spectrum of the ADCY10 gene and provides a potential diagnostic and therapeutic target.

Identification of mutations in 15 nephrolithiasis-related genes leading to a molecular diagnosis in 85 Chinese pediatric patients.

BACKGROUND: The aim of this study was to describe the genotypic and phenotypic characteristics of Chinese pediatric patients with hereditary nephrolithiasis. METHODS: Whole-exome sequencing (WES) was performed on 218 Chinese pediatric patients with kidney stones, and genetic and clinical data were collected and analyzed retrospectively. RESULTS: The median age at onset in our cohort was 2.5 years (age range, 0.3-13 years). We detected 79 causative mutations in 15 genes, leading to a molecular diagnosis in 38.99% (85/218) of all cases. Monogenic mutations were present in 80 cases, and digenic mutations were present in 5 cases; 34.18% (27/79) of mutations were not included in the databases. Six common mutant genes, i.e., HOGA1, AGXT, GRHPR, SLC3A1, SLC7A9, and SLC4A1, were found in 84.71% of the patients overall. Furthermore, three mutations (A278A, c.834_834 + 1GG > TT, and C257G) in HOGA1, two mutations (K12QfX156 and S275RfX28) in AGXT, and one mutation (C289DfX22) in GRHPR represented hotspot mutations. The patients with HOGA1 mutations had the earliest onset age (0.8 years), followed by those with SLC7A9 (1.8 years), SLC4A1 (2.7 years), AGXT (4.3 years), SLC3A1 (4.8 years), and GRHPR (8 years) mutations (p = 0.002). Nephrocalcinosis was most commonly observed in patients with AGXT gene mutations. CONCLUSIONS: Fifteen causative genes were detected in 85 Chinese pediatric patients with kidney stone diseases. The most common mutant genes, novel mutations, hotspot mutations, and genotype-phenotype correlations were also found. This study contributes to the understanding of genetic profiles and clinical courses in pediatric patients with hereditary nephrolithiasis. A higher resolution version of the Graphical abstract is available as Supplementary information.

HOGA1 variants in Chinese patients with primary hyperoxaluria type 3: genetic features and genotype-phenotype relationships.

PURPOSE: The aim of our study is to describe the genetic features and correlation between the genotype and phenotype of Chinese patients with primary hyperoxaluria type 3 (PH3). METHODS: The genetic and clinical data of PH3 patients in our cohort were collected and analyzed retrospectively. All published studies of Chinese PH3 populations between January 2010 and November 2022 were searched and enrolled based on inclusive standards. RESULTS: A total of 60 Chinese PH3 patients (21 cases from our cohort and 39 cases from previous studies) were included. The mean age of onset was 1.62 ± 1.35 (range 0.4-7) years. A total of 29 different variants in the HOGA1 gene were found. The mutations were most commonly clustered in exons 1, 6, and 7. Among the genotypes, exon 6 skipping (c.834G > A and c.834_834 + 1GG > TT mutations) was the most common, followed by c.769 T > G; the allele frequencies (AFs) were 48.76% and 12.40%, respectively. Patients homozygous for exon 6 skipping exhibited a median age of onset of 0.67 (0.58-1) years, which was significantly lower than that observed among heterozygotes and nonexon 6 skipping patients (p = 0.021). A total of 22.5% (9/40) of PH3 patients had a decreased estimated glomerular filtration rate, and one patient with homozygous exon 6 skipping developed end-stage renal disease. CONCLUSIONS: A hotspot mutation, potential hotspot mutation and genotype-phenotype correlation were found in Chinese PH3 patients. This study expands the mutational spectrum and contributes to the understanding of genotypic profiles of PH3, which may provide a potential diagnostic and therapeutic target.

Microureteroscopy in the treatment of upper urinary tract stones in pediatric patients younger than 3 years of age.

The aim of this study is to evaluate the usefulness of microureteroscopy (m-URS) in the treatment of renal and ureteral stones in children younger than 3 years of age. A retrospective analysis of pediatric patients aged < 3 years with upper urinary tract calculi who underwent lithotripsy was performed. The children were divided into the m-URS group (4.85 F, n = 41) and the ureteroscopy (URS) group (4.5/6.5 F, n = 42) according to the type of ureteroscope used. The mean age of the patients was 23.5 ± 10.7 months in the m-URS group and 20.6 ± 7.1 months in the URS group (P = 0.212). The success rate of one-stage surgery was 80.5% (33/41) for m-URS and 38.1% (16/42) for URS (P < 0.001). The success rates of m-URS were 60.0%, 69.2%, and 91.3% for stones located in the renal pelvis/calix, upper ureter, and mid-lower ureter, respectively. Eight children in the m-URS group and 26 children in the URS group underwent the second-stage ureteroscopic surgery. The mean operation time was 50 (30-60) min in the m-URS group and 40 (34-60) min in the URS group (P = 0.287). The complication rates were 4.9% and 7.1% in the m-URS and URS groups, respectively (P = 1.000). The stone-free rate at 1 month after lithotripsy was 87.8% in the m-URS group and 83.3% in the URS group (P = 0.563). The mean anesthesia session was 2.1 in the m-URS group and 2.5 in the URS group (P = 0.002). M-URS can effectively reduce the number of anesthesia sessions and is considered an alternative treatment for upper urinary tract calculi in selected pediatric patients younger than 3 years of age.

Genetic and clinical analysis of Chinese pediatric patients with cystinuria.

This study aimed to investigate the genotypic and phenotypic characteristics of Chinese pediatric patients with cystinuria. This was a retrospective study of 14 Chinese pediatric patients with cystine stones. All published studies of the Chinese pediatric cystinuria population were searched and enrolled based on the inclusive standard. Among the 14 pediatric patients with cystinuria, 8 were males and 6 were females. The mean age of first stone onset was 4.0 ± 3.3 years (4 months-9 years). All of the patients had multiple stones, and 57.1% (8/14) had bilateral stones. The mean maximum stone diameter was 1.7 ± 0.6 (range 0.5-2.6) cm. A total of 13 SLC3A1 gene mutations and 9 SLC7A9 gene mutations were detected, of which 41% (9/22) of mutations were novel. Patients with SLC7A9 mutations were more likely to develop bilateral stones than those with SLC3A1 mutations (100% vs. 33.3%, p = 0.03). Thirty-four SLC3A1 gene mutations and twenty-eight SLC7A9 gene mutations were found in a total of fifty-five Chinese children with cystinuria. The SLC7A9 gene mutation distribution was more dispersed, while the SLC3A1 mutation was clustered in exons 6-8. The c.647C > T (p. T216M) (4/53) and c.1113C > A (p. Y371Ter) (4/53) mutations in the SLC3A1 gene and the c.1399 + 2_3insT (3/36) mutation in the SLC7A9 gene represent potential hotspots in cystinuria. Our results present a comprehensive genetic spectrum for pediatric cystinuria patients in China. Patients with SLC7A9 mutations were more likely to develop bilateral stones than those with SLC3A1 mutations. A wide mutation spectrum and the potential mutation hotspots associated with cystinuria were also identified.