title: Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study.
abstract: Renal hypodysplasia (RHD) is characterized by a reduced nephron number, small kidney size, and disorganized renal tissue. A hereditary basis has been established for a subset of affected patients, suggesting a major role of developmental genes that are involved in early kidney organogenesis. Gene mutations that have dominant inheritance and cause RHD, urinary tract anomalies, and defined extrarenal symptoms have been identified in TCF2 (renal cysts and diabetes syndrome), PAX2 (renal-coloboma syndrome), EYA1 and SIX1 (branchio-oto-renal syndrome), and SALL1 (Townes-Brocks syndrome). For estimation of the prevalence of these events, an unselected cohort of 99 unrelated patients with RHD that was associated with chronic renal insufficiency were screened for mutations in TCF2, PAX2, EYA1, SIX1, and SALL1. Mutations or variants in the genes of interest were detected in 17 (17%) unrelated families: One mutation, two variants, and four deletions of TCF2 in eight unrelated patients; four different PAX2 mutations in six families; one EYA1 mutation and one deletion in two patients with branchio-oto-renal syndrome; and one SALL1 mutation in a patient with isolated RHD. Of a total of 27 patients with renal cysts, six (22%) carried a mutation in TCF2. It is interesting that a SIX1 sequence variant was identified in two siblings with renal-coloboma syndrome as a result of a PAX2 mutation, suggesting an oligogenic inheritance. Careful clinical reevaluation that focused on discrete extrarenal symptoms and thorough family analysis revealed syndrome-specific features in nine of the 17 patients. In conclusion, 15% of patients with RHD show mutations in TCF2 or PAX2, whereas abnormalities in EYA1, SALL1, and SIX1 are less frequent.
authors.affiliation: Department of Pediatric Nephrology, Hôpital Necker-Enfants Malades, Université René Descartes, 147 Rue de Sèvres, 75015 Paris, France.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
authors.forename: Vincent
authors.initials: V
authors.lastname: Moriniere
authors.forename: Tanja
authors.initials: T
authors.lastname: Knüppel
authors.forename: Marina
authors.initials: M
authors.lastname: Charbit
authors.forename: Jirí
authors.initials: J
authors.lastname: Dusek
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: Augustina
authors.initials: A
authors.lastname: Jankauskiené
authors.forename: Sevgi
authors.initials: S
authors.lastname: Mir
authors.forename: Giovanni
authors.initials: G
authors.lastname: Montini
authors.forename: Amira
authors.initials: A
authors.lastname: Peco-Antic
authors.forename: Elke
authors.initials: E
authors.lastname: Wühl
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Zurowska
authors.forename: Otto
authors.initials: O
authors.lastname: Mehls
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Remi
authors.initials: R
authors.lastname: Salomon
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D021782:Multicystic Dysplastic Kidney / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D051762:PAX2 Transcription Factor / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C496495:HNF1B protein, human; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; C104146:SALL1 protein, human; C099236:SIX1 protein, human; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases