Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.
Bibliographical noteFunding Information:
We thank the families who contributed to this study and the physicians who contributed clinical data, Davut Pehlivan, MD; Clifford Kashtan, MD; Judy Henry, MD; KE Bonzel, MD; Volker Klingmueller, MD; and Richard A Lewis, MD. We thank Robert H Lyons for excellent Sanger sequencing. This research was supported by grants from the National Institutes of Health to FH (DK1069274, DK1068306, DK064614) and to NK (HD042601, DK075972, DK072301) and by grants from the European Community's Seventh Framework Programme FP7/2009 under grant agreement no: 241955, SYSCILIA to NK. HYG is a research fellow of the American Society of Nephrology (ASN). NK is a distinguished Jean and George Brumley Professor. FH is a Warren Grupe Professor of Pediatrics and an investigator of the Howard Hughes Medical Institute.
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