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Kidney Int. 2014 Jun;85(6):1429-33. doi: 10.1038/ki.2013.508. Epub 2014 Jan 15.

Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract.

Author information

1
1] Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
2
1] Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Institute of Human Genetics, University of Bonn, Bonn, Germany.
3
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
5
Institute of Human Genetics, University of Bonn, Bonn, Germany.
6
1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany.
7
1] Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt [2] Egyptian Group for Orphan Renal Diseases (EGORD), Cairo, Egypt.
8
Medical Faculty, University of Belgrade, Belgrade, Serbia.
9
Department of Surgery, Kuwait University, Safat, Kuwait.
10
Department of Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia.
11
1] Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease. CAKUT can be caused by monogenic mutations; however, data are lacking on their frequency. Genetic diagnosis has been hampered by genetic heterogeneity and lack of genotype-phenotype correlation. To determine the percentage of cases with CAKUT that can be explained by mutations in known CAKUT genes, we analyzed the coding exons of the 17 known dominant CAKUT-causing genes in a cohort of 749 individuals from 650 families with CAKUT. The most common phenotypes in this CAKUT cohort were vesicoureteral reflux in 288 patients, renal hypodysplasia in 120 patients, and unilateral renal agenesis in 90 patients. We identified 37 different heterozygous mutations (33 novel) in 12 of the 17 known genes in 47 patients from 41 of the 650 families (6.3%). These mutations include (number of families): BMP7 (1), CDC5L (1), CHD1L (5), EYA1 (3), GATA3 (2), HNF1B (6), PAX2 (5), RET (3), ROBO2 (4), SALL1 (9), SIX2 (1), and SIX5 (1). Furthermore, several mutations previously reported to be disease-causing are most likely benign variants. Thus, in a large cohort over 6% of families with isolated CAKUT are caused by a mutation in 12 of 17 dominant CAKUT genes. Our report represents one of the most in-depth diagnostic studies of monogenic causes of isolated CAKUT in children.

PMID:
24429398
PMCID:
PMC4040148
DOI:
10.1038/ki.2013.508
[Indexed for MEDLINE]
Free PMC Article

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