Background. Alport syndrome (AS) and atypical hemolytic- uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. Methods. We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. Results. We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%). Conclusions. We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.
Bibliographical noteFunding Information:
F.H. is a cofounder of Goldfinch Bio and receives royalties from Claritas Genomics. E.W. reports grants from the National Institutes of Health and the German National Academy of Sciences Leopoldina during the conduct of the study. Neither this manuscript nor substantial parts of it are under consideration for publication elsewhere. Twenty-two families analyzed in this study were independently and previously published, either as index families in papers describing novel SRNS-causing genes or in our previous high-throughput exon sequencing paper on monogenic forms of SRNS ; however, none of the families included in this study had previously been analyzed comprehensively for ASor aHUS-causing mutations.
This research was supported by grants from the National Institutes of Health (DK076683 to F.H.), Harvard Stem Cell Institute and National Institutes of Health (T32DK007726-31A1 to A.J.M.), Deutsche Forschungsgemeinschaft (JO 1324/ 1-1 to T.J.S.) and German Research Foundation (VE 916/1-1 to A.T.v.d.V.). Deutsche Forschungsgemeinschaft (HE 7456/ 1-1 to T.H.) and German National Academy of Sciences Leopoldina (LPDS 2015-07 to E.W.) and American Society of Nephrology (Benjamin J. Lipps Research Fellowship Award FP01014311 to W.T.).
© 2018 The Author(s).
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