Abstract
Kidney disease is manifested in a wide variety of phenotypes, many of which have an important hereditary component. To delineate the genotypic and phenotypic spectrum of pediatric nephropathy, a multicenter registration system is being implemented based on the Chinese Children Genetic Kidney Disease Database (CCGKDD). In this study, all the patients with kidney and urological diseases were recruited from 2014 to 2020. Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features. The genetic diagnosis was confirmed in 883 of 2256 (39.1%) patients from 23 provinces in China. Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome (SRNS, 23.5%), glomerulonephritis (GN, 32.2%), congenital anomalies of the kidney and urinary tract (CAKUT, 21.2%), cystic renal disease (3.9%), renal calcinosis/stone (3.6%), tubulopathy (9.7%), and chronic kidney disease of unknown etiology (CKDu, 5.8%). The pathogenic variants of 105 monogenetic disorders were identified. Ten distinct genomic disorders were identified as pathogenic copy number variants (CNVs) in 11 patients. The diagnostic yield differed by subgroups, and was highest in those with cystic renal disease (66.3%), followed by tubulopathy (58.4%), GN (57.7%), CKDu (43.5%), SRNS (29.2%), renal calcinosis /stone (29.3%) and CAKUT (8.6%). Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions. We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed. Our data demonstrate the utility of family-based exome sequencing, and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.
Highlights
Chronic kidney disease (CKD) is a broad term that encompasses many complex disorders that collectively affect over 1 in 10 individuals worldwide, resulting in substantial morbidity and mortality as well as the high1 3 Vol.:(0123456789)healthcare costs
Patients who are less than 25 years old with a positive family history or early-onset kidney disease or extrarenal features are encouraged to receive genetic detection, and the consent was previously obtained from each guardian of the patients
Children and adolescents with kidney and urological diseases from 0 to 18 years of age were prospectively recruited between January 2014 and November 2020 based on the data from the Chinese Children Genetic Kidney Disease Database (CCGKDD)
Summary
Chronic kidney disease (CKD) is a broad term that encompasses many complex disorders that collectively affect over 1 in 10 individuals worldwide, resulting in substantial morbidity and mortality as well as the high1 3 Vol.:(0123456789)healthcare costs. See “Methods” and “Online Resource 2” for details population (Saran et al 2020; Connaughton et al 2019), and other indices of kidney function, such as albuminuria and electrolyte excretion, show similar significant heritability (Stevens et al 2013; Hays et al 2020). It is important for all those involved in either the care of patients with kidney disease or the study of the kidney to have a basic understanding of the spectrum of variation and the breadth of phenotypes that are relevant to kidney health and disease
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