Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.
Bibliographical noteFunding Information:
We thank the physicians and the participating families for their contribution. FH is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and the Warren E. Grupe Professor of Pediatrics. This research was supported by grants from the National Institutes of Health (DK1069274, DK1068306, and DK064614 to FH; DK099434 to RA, 5U54HG006504 to RPL) and by the March of Dimes Foundation (6-FY11-241 to FH). HYG is supported by the ASN-NephCure Foundation grant. BBB acknowledges funding from university endowments of the Faculty of Medicine (Stiftungsgelder Imhoff-Stifung). FO is supported by the European Community's Seventh Framework Programme (FP7/2007-2013) (EURenOmics; grant 2012-305608). The Nephrogenetics Laboratory at Hacettepe University was established by the Hacettepe University Infrastructure Project (grant number 06A101008).
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