New insights into pediatric genetic kidney disease

doi:10.3877/cma.j.issn.2095-3216.2026.01.002

Abstract

Abstract:

Over the past two decades, the widespread application of genetic testing technologies, particularly the clinical implementation of next-generation sequencing, has profoundly reshaped the understanding of genetic kidney diseases in children. This technological advancement has significantly improved the diagnostic yield for genetic kidney diseases in both adults and children, accelerating the discovery and identification of pathogenic genes, while continuously expanding and refining the genotype-phenotype correlations of classical renal disorders. These advances have driven the updating and reclassification of genetic kidney diseases, shifting the clinical management paradigm from a traditional phenotype-oriented approach to a precision medicine model centered on genetic variants, pathophysiological mechanisms, and molecular etiologies. Based on the renewed understanding of the pathogenesis and clinical heterogeneity of genetic kidney diseases, this article systematically reviews and analyzes the evolving genotype-phenotype spectra of several typical pediatric genetic kidney diseases. Furthermore, it proposes recommendations regarding the indications for genetic testing in clinical practice of pediatric nephrology, aiming to provide a reference for the precise diagnosis and treatment of these disorders.

Key words: Genetic kidney disease, Children, Genotype-phenotype spectrum, Heterogeneity, Pathogenesis

Hui Wang, Yongqi Sun. New insights into pediatric genetic kidney disease[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2026, 15(01): 8-14.

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References 49

[1]	Rasouly HM, Groopman EE, Heyman-Kantor R, et al. The burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing [J]. Ann Intern Med, 2019, 170(1): 11-21.
[2]	Groopman EE, Marasa M, Cameron-Christie S, et al. Diagnostic utility of exome sequencing for kidney disease [J]. N Engl J Med, 2019, 380(2): 142-151.
[3]	Dahl NK, Bloom MS, Chebib FT, et al. The clinical utility of genetic testing in the diagnosis and management of adults with chronic kidney disease [J]. J Am Soc Nephrol, 2023, 34(12): 2039-2050.
[4]	Devuyst O, Knoers NVAM, Remuzzi G, et al. Rare inherited kidney diseases: challenges, opportunities, and perspectives [J]. Lancet, 2014, 383(9931): 1844-1859.
[5]	Mann N, Braun DA, Amann K, et al. Whole-exome sequencing enables a precision medicine approach for kidney transplant recipients [J]. J Am Soc Nephrol, 2019, 30(2): 201-215.
[6]	Ben-Moshe Y, Shlomovitz O, Atias-Varon D, et al. Diagnostic utility of exome sequencing among Israeli children with kidney failure [J]. Kidney Int Rep, 2023, 8(10): 2126-2135.
[7]	Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease [J]. Kidney Int, 2024, 105(4S): S117-S314.
[8]	Vivante A. Genetics of chronic kidney disease [J]. N Engl J Med, 2024, 391(7): 627-639.
[9]	Li AS, Ingham JF, Lennon R. Genetic disorders of the glomerular filtration barrier [J]. Clin J Am Soc Nephrol, 2020, 15(12): 1818-1828.
[10]	Pollak MR, Friedman DJ. The genetic architecture of kidney disease [J]. Clin J Am Soc Nephrol, 2020, 15(2): 268-275.
[11]	Groopman EE, Povysil G, Goldstein DB, et al. Rare genetic causes of complex kidney and urological diseases [J]. Nat Rev Nephrol, 2020, 16(11): 641-656.
[12]	Sanchez-Rodriguez E, Southard CT, Kiryluk K. GWAS-based discoveries in IgA nephropathy, membranous nephropathy, and steroid-sensitive nephrotic syndrome [J]. Clin J Am Soc Nephrol, 2021, 16(3): 458-466.
[13]	Friedman DJ, Pollak MR. Apolipoprotein L1 and kidney disease in African Americans [J]. Trends Endocrinol Metab, 2016, 27(4): 204-215.
[14]	Xie J, Liu L, Mladkova N, et al. The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis [J]. Nat Commun, 2020, 11(1): 1600.
[15]	丁西满，王世然. 遗传性肾脏病的分类和临床研究近况[J]. 国外医学遗传学分册，1986, (3): 123-126.
[16]	Drovandi S, Lipska-Ziętkiewicz BS, Ozaltin F, et al. Oral coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary coenzyme Q10 deficiency [J]. Kidney Int, 2022, 102(3): 604-612.
[17]	戴阳丽，罗小平，巩纯秀，等. 中国儿童Bardet-Biedl综合征诊治专家共识[J]. 中国实用儿科杂志，2022, 37(4): 241-247.
[18]	Muntean C, Chirtes C, Baczoni B, et al. PAX2 gene mutation in pediatric renal disorders-a narrative review [J]. Int J Mol Sci, 2023, 24(16): 12737.
[19]	Adam J, Browning AC, Vaideanu D, et al. A wide spectrum of phenotypes in a family with renal coloboma syndrome caused by a PAX2 mutation [J]. Clin Kidney J, 2013, 6(4): 410-413.
[20]	Ozaltin F, Li B, Rauhauser A, et al. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN [J]. J Am Soc Nephrol, 2013, 24(3): 377-384.
[21]	Lemaire M, Frémeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome [J]. Nat Genet, 2013, 45(5): 531-536.
[22]	Kashtan CE. Alport syndrome: achieving early diagnosis and treatment [J]. Am J Kidney Dis, 2021, 77(2): 272-279.
[23]	Deltas C, Pierides A. COL4A3/COL4A4 heterozygous mutations with TBMN presenting as focal segmental glomerulosclerosis [J]. Kidney Int, 2015, 87(4): 859.
[24]	Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis [J]. Kidney Int, 2014, 86(6): 1253-1259.
[25]	Funk SD, Lin MH, Miner JH. Alport syndrome and pierson syndrome: diseases of the glomerular basement membrane [J]. Matrix Biol, 2018, 71-72: 250-261.
[26]	Savige J, Harraka P. Pathogenic LAMA5 variants and kidney disease [J]. Kidney360, 2021, 2(12): 1876-1879.
[27]	Goldberg S, Adair-Kirk TL, Senior RM, et al. Maintenance of glomerular filtration barrier integrity requires laminin alpha5 [J]. J Am Soc Nephrol, 2010, 21(4): 579-586.
[28]	Kaimori JY, Kikkawa Y, Motooka D, et al. A heterozygous LAMA5 variant may contribute to slowly progressive, vinculin-enhanced familial FSGS and pulmonary defects [J]. JCI Insight, 2022, 7(23): e158378.
[29]	Deepthi B, Sivakumar RR, Krishnasamy S, et al. Congenital nephrotic syndrome with diffuse mesangial sclerosis caused by compound heterozygous mutation in LAMA5 gene [J]. Pediatr Nephrol, 2024, 39(5): 1421-1425.
[30]	Sunwoo Y, Choi N, Min J, et al. Case report: genetic defects in laminin α5 cause infantile steroid-resistant nephrotic syndrome [J]. Front Pediatr, 2022, 10: 1054082.
[31]	Voskarides K, Papagregoriou G, Hadjipanagi D, et al. COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect? [J]. BMC Nephrol, 2018, 19(1): 114.
[32]	Daga S, Fallerini C, Furini S, et al. Non-collagen genes role in digenic Alport syndrome [J]. BMC Nephrol, 2019, 20(1): 70.
[33]	Trautmann A, Bodria M, Ozaltin F, et al. Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort [J]. Clin J Am Soc Nephrol, 2015, 10(4): 592-600.
[34]	Bierzynska A, McCarthy HJ, Soderquest K, et al. Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management [J]. Kidney Int, 2017, 91(4): 937-947.
[35]	Meliambro K, He JC, Campbell KN. Podocyte-targeted therapies- progress and future directions [J]. Nat Rev Nephrol, 2024, 20(10): 643-658.
[36]	Jungraithmayr TC, Hofer K, Cochat P, et al. Screening for NPHS2 mutations may help predict FSGS recurrence after transplantation [J]. J Am Soc Nephrol, 2011, 22(3): 579-585.
[37]	Falcone MP, Pritchard-Jones K, Brok J, et al. Long-term kidney function in children with Wilms tumour and constitutional WT1 pathogenic variant [J]. Pediatr Nephrol, 2022, 37(4): 821-832.
[38]	McConnachie DJ, Stow JL, Mallett AJ. Ciliopathies and the kidney: a review [J]. Am J Kidney Dis, 2021, 77(3): 410-419.
[39]	Anvarian Z, Mykytyn K, Mukhopadhyay S, et al. Cellular signalling by primary cilia in development, organ function and disease [J]. Nat Rev Nephrol, 2019, 15(4): 199-219.
[40]	Hildebrandt F, Benzing T, Katsanis N. Ciliopathies [J]. N Engl J Med, 2011, 364(16): 1533-1543.
[41]	Tory K, Lacoste T, Burglen L, et al. High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations [J]. J Am Soc Nephrol, 2007, 18(5): 1566-1575.
[42]	Reiter JF, Leroux MR. Genes and molecular pathways underpinning ciliopathies [J]. Nat Rev Mol Cell Biol, 2017, 18(9): 533-547.
[43]	孙咏琪，王辉. HNF1B肾病及其肾脏囊性表型发生机制研究进展[J]. 中华儿科杂志，2025, 63(11): 1270-1274.
[44]	Faguer S, Decramer S, Chassaing N, et al. Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood [J]. Kidney Int, 2011, 80(7): 768-776.
[45]	Goknar N, Ekici Avci M, Uckardes D, et al. Hepatocyte nuclear factor 1 beta mutation-associated newborn onset of glomerulocystic kidney disease: a case presentation [J]. Medeni Med J, 2021, 36(4): 352-355.
[46]	Groopman EE, Rasouly HM, Gharavi AG. Genomic medicine for kidney disease [J]. Nat Rev Nephrol, 2018, 14(2): 83-104.
[47]	KDIGO Conference Participants. Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference [J]. Kidney Int, 2022, 101(6): 1126-1141.
[48]	Franceschini N, Feldman DL, Berg JS, et al. Advancing genetic testing in kidney diseases: report from a National Kidney Foundation Working Group [J]. Am J Kidney Dis, 2024, 84(6): 751-766.
[49]	Savige J, Lipska-Zietkiewicz BS, Watson E, et al. Guidelines for genetic testing and management of Alport syndrome [J]. Clin J Am Soc Nephrol, 2022, 17(1): 143-154.

临床应用	解释和举例说明
缩短诊断时间	对于提示可能存在遗传性肾脏病的患者，早期进行基因检测有助于明确诊断，缩短诊断花费时间，减少患者就医负担，例如SRNS等。
靶向监测并治疗肾外异常	HNF1B变异可导致一系列肾外表现，如糖尿病、肝功能损伤、生殖系统畸形等，与CAKUT相关的基因EYA1、SALL1或PAX2变异可能表现为听力异常，明确遗传学诊断可早期发现这些症状隐匿的疾病，尽早治疗。
指导临床治疗	SRNS患者中约30%存在单基因变异，早期进行基因检测明确遗传学诊断有助于制定正确的治疗方案，例如CoQ10合成相关基因缺陷导致的肾病综合征，尽早补充大剂量CoQ10可明显改善预后。
避免过度检查和治疗	对于病因不明CKD、SRNS患者优先进行基因检测明确诊断，如发现存在相关致病变异如NPHS1、NPHS2或NPHP1等，可避免进行肾活检；HNF1B变异患者可能存在肝功能异常，此为HNF1B变异相关表型的一部分，应避免如肝活检等不必要的侵入性检查。
评估疾病预后	对于某些基因，变异类型能够提供疾病进展和预后的信息，例如，Alport综合征或常染色体显性多囊肾病中，无义变异通常较错义变异患者肾脏预后更差；17q12微片段缺失较HNF1B基因点突变患者肾脏预后更好。
家系成员早期筛查，提供遗传咨询	部分遗传性肾脏病患者在疾病早期阶段可能无症状，如PAX2突变患者，通过基因检测明确家庭中某一成员的遗传学诊断后，可提醒其他家族成员尽早完善相关检查，早期发现病变并进行干预，同时指导计划生育和遗传咨询。

临床应用	解释和举例说明
缩短诊断时间	对于提示可能存在遗传性肾脏病的患者，早期进行基因检测有助于明确诊断，缩短诊断花费时间，减少患者就医负担，例如SRNS等。
靶向监测并治疗肾外异常	HNF1B变异可导致一系列肾外表现，如糖尿病、肝功能损伤、生殖系统畸形等，与CAKUT相关的基因EYA1、SALL1或PAX2变异可能表现为听力异常，明确遗传学诊断可早期发现这些症状隐匿的疾病，尽早治疗。
指导临床治疗	SRNS患者中约30%存在单基因变异，早期进行基因检测明确遗传学诊断有助于制定正确的治疗方案，例如CoQ10合成相关基因缺陷导致的肾病综合征，尽早补充大剂量CoQ10可明显改善预后。
避免过度检查和治疗	对于病因不明CKD、SRNS患者优先进行基因检测明确诊断，如发现存在相关致病变异如NPHS1、NPHS2或NPHP1等，可避免进行肾活检；HNF1B变异患者可能存在肝功能异常，此为HNF1B变异相关表型的一部分，应避免如肝活检等不必要的侵入性检查。
评估疾病预后	对于某些基因，变异类型能够提供疾病进展和预后的信息，例如，Alport综合征或常染色体显性多囊肾病中，无义变异通常较错义变异患者肾脏预后更差；17q12微片段缺失较HNF1B基因点突变患者肾脏预后更好。
家系成员早期筛查，提供遗传咨询	部分遗传性肾脏病患者在疾病早期阶段可能无症状，如PAX2突变患者，通过基因检测明确家庭中某一成员的遗传学诊断后，可提醒其他家族成员尽早完善相关检查，早期发现病变并进行干预，同时指导计划生育和遗传咨询。

a)	肾脏疾病、透析或肾移植家族史
b)	伴有肾外表现或多系统异常/综合征
c)	发病年龄早或不明原因的CKD
d)	不明原因慢性肾小球性血尿^a、慢性蛋白尿^b
e)	肾脏结构异常，如囊性肾脏病和CAKUT等
f)	先天性、激素耐药或治疗不顺利的肾病综合征
g)	反复发作的电解质紊乱或肾结石
h)	肾脏病理活检提示存在遗传性疾病，如不明原因的慢性肾小管间质疾病、无明确继发原因的FSGS、系膜增生性肾小球肾炎、符合Ⅳ型胶原相关肾病的肾小球基底膜异常、血栓性微血管病、脂质沉积等
i)	临床怀疑或临床诊断特定遗传性肾脏病

a)	肾脏疾病、透析或肾移植家族史
b)	伴有肾外表现或多系统异常/综合征
c)	发病年龄早或不明原因的CKD
d)	不明原因慢性肾小球性血尿^a、慢性蛋白尿^b
e)	肾脏结构异常，如囊性肾脏病和CAKUT等
f)	先天性、激素耐药或治疗不顺利的肾病综合征
g)	反复发作的电解质紊乱或肾结石
h)	肾脏病理活检提示存在遗传性疾病，如不明原因的慢性肾小管间质疾病、无明确继发原因的FSGS、系膜增生性肾小球肾炎、符合Ⅳ型胶原相关肾病的肾小球基底膜异常、血栓性微血管病、脂质沉积等
i)	临床怀疑或临床诊断特定遗传性肾脏病

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