title: Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract.
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.
authors.affiliation: 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.
authors.forename: Daw-Yang
authors.initials: DY
authors.lastname: Hwang
authors.affiliation: 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.
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Dworschak
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Pawaree
authors.initials: P
authors.lastname: Saisawat
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Asaf
authors.initials: A
authors.lastname: Vivante
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alina C
authors.initials: AC
authors.lastname: Hilger
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany.
authors.forename: Heiko M
authors.initials: HM
authors.lastname: Reutter
authors.affiliation: 1] Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt [2] Egyptian Group for Orphan Renal Diseases (EGORD), Cairo, Egypt.
authors.forename: Neveen A
authors.initials: NA
authors.lastname: Soliman
authors.affiliation: Medical Faculty, University of Belgrade, Belgrade, Serbia.
authors.forename: Radovan
authors.initials: R
authors.lastname: Bogdanovic
authors.affiliation: Department of Surgery, Kuwait University, Safat, Kuwait.
authors.forename: Elijah O
authors.initials: EO
authors.lastname: Kehinde
authors.affiliation: Department of Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia.
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: 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.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D014564:Urogenital Abnormalities; D014718:Vesico-Ureteral Reflux / Q000235:genetics*