Division of Nephrology, Department of Pediatrics, Cohen Children's Medical Center, 269-01 76th Ave, Queens, NY, 11040, USA.
Division of Nephrology, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Pediatr Nephrol. 2023 Aug;38(8):2615-2622. doi: 10.1007/s00467-023-05879-0. Epub 2023 Jan 23.
Diagnosing genetic kidney disease has become more accessible with low-cost, rapid genetic testing. The study objectives were to determine genetic testing diagnostic yield and examine predictors of genetic diagnosis in children with nephrolithiasis/nephrocalcinosis (NL/NC).
This retrospective multicenter cross-sectional study was conducted on children ≤ 21 years old with NL/NC from pediatric nephrology/urology centers that underwent the Invitae Nephrolithiasis Panel 1/1/2019-9/30/2021. The diagnostic yield of the genetic panel was calculated. Bivariate and multiple logistic regression were performed to assess for predictors of positive genetic testing.
One hundred and thirteen children (83 NL, 30 NC) from 7 centers were included. Genetic testing was positive in 32% overall (29% NL, 40% NC) with definite diagnoses (had pathogenic variants alone) made in 11.5%, probable diagnoses (carried a combination of pathogenic variants and variants of uncertain significance (VUS) in the same gene) made in 5.4%, and possible diagnoses (had VUS alone) made in 15.0%. Variants were found in 28 genes (most commonly HOGA1 in NL, SLC34A3 in NC) and 20 different conditions were identified. Compared to NL, those with NC were younger and had a higher proportion with developmental delay, hypercalcemia, low serum bicarbonate, hypophosphatemia, and chronic kidney disease. In multivariate analysis, low serum bicarbonate was associated with increased odds of genetic diagnosis (β 2.2, OR 8.7, 95% CI 1.4-54.7, p = 0.02).
Genetic testing was high-yield with definite, probable, or possible explanatory variants found in up to one-third of children with NL/NC and shows promise to improve clinical practice. A higher resolution version of the Graphical abstract is available as Supplementary information.
随着低成本、快速基因检测的出现，遗传性肾脏疾病的诊断变得更加便捷。本研究旨在确定基因检测的诊断率，并探讨肾结石/肾钙质沉着症（NL/NC）患儿基因诊断的预测因素。
本回顾性多中心横断面研究纳入了 2019 年 1 月 1 日至 2021 年 9 月 30 日期间在儿科肾病/泌尿科中心接受 Invitae 肾结石症 panel 检测的≤21 岁 NL/NC 患儿。计算基因panel 的诊断率。采用二变量和多变量逻辑回归评估阳性基因检测的预测因素。
本研究共纳入了 7 个中心的 113 名患儿（83 名 NL，30 名 NC）。总体而言，基因检测阳性率为 32%（NL 为 29%，NC 为 40%），其中明确诊断（仅携带致病性变异）占 11.5%，可能诊断（携带致病性变异和同一基因中的不确定意义变异（VUS）的组合）占 5.4%，可能诊断（仅携带 VUS）占 15.0%。在 28 个基因中发现了变异（NL 中最常见的是 HOGA1，NC 中最常见的是 SLC34A3），并确定了 20 种不同的疾病。与 NL 相比，NC 患儿更年轻，且有更高比例的患儿伴有发育迟缓、高钙血症、低血清碳酸氢盐、低磷血症和慢性肾脏病。多变量分析显示，低血清碳酸氢盐与基因诊断的可能性增加相关（β 2.2，OR 8.7，95%CI 1.4-54.7，p=0.02）。
基因检测的诊断率较高，在多达三分之一的 NL/NC 患儿中发现了明确、可能或可能的解释性变异，有望改善临床实践。
