Shan Elahi1, Alison Homstad1,2, Himani Vaidya1,2, Jennifer Stout1, Gentzon Hall2,3, Guanghong Wu2,3, Peter Conlon1, Jonathan C Routh1,4, John S Wiener1,4, Sherry S Ross4,5, Shashi Nagaraj1, Delbert Wigfall1, John Foreman1, Adebowale Adeyemo6, Indra R Gupta7, Patrick D Brophy8, C Egla Rabinovich1, Rasheed A Gbadegesin9,10. 1. Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. 2. Duke Molecular Physiology Institute, Durham, NC, USA. 3. Department of Medicine, Duke University Medical Center, Durham, NC, USA. 4. Department of Surgery, Division of Urology, Duke University Medical Center, Durham, NC, USA. 5. Department of Urology, Pediatric Urology, UNC School of Medicine , University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 6. Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892-5635, USA. 7. Department of Pediatrics and Human Genetics, McGill University, Montreal, QC, Canada. 8. Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA. 9. Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. rasheed.gbadegesin@duke.edu. 10. Duke Molecular Physiology Institute, Durham, NC, USA. rasheed.gbadegesin@duke.edu.
Abstract
BACKGROUND: Primary vesicoureteral reflux (PVUR) is the most common malformation of the kidney and urinary tract, and reflux nephropathy is a major cause of chronic kidney disease in children. Recently, we reported mutations in the tenascin XB gene (TNXB) as a cause of PVUR with joint hypermobility. METHODS: To define the role of rare variants in tenascin genes in the etiology of PVUR, we screened a cohort of patients with familial PVUR (FPVUR) and non-familial PVUR (NFPVUR) for rare missense variants inTNXB and the tenascin C gene (TNC) after excluding mutations in ROBO2 and SOX17. RESULTS: The screening procedure identified 134 individuals from 112 families with PVUR; two families with mutations in ROBO2 were excluded from further analysis. Rare missense variants in TNXB were found in the remaining 110 families, of which 5/55 (9%) families had FPVUR and 2/55 (4%) had NFPVUR. There were no differences in high-grade reflux or renal parenchymal scarring between patients with and without TNXB variants. All patients with TNXB rare variants who were tested exhibited joint hypermobility. Overall we were able to identify causes of FPVUR in 7/57 (12%) families (9% in TNXB and 3% in ROBO2). CONCLUSIONS: In conclusion, the identification of a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts.
BACKGROUND: Primary vesicoureteral reflux (PVUR) is the most common malformation of the kidney and urinary tract, and reflux nephropathy is a major cause of chronic kidney disease in children. Recently, we reported mutations in the tenascin XB gene (TNXB) as a cause of PVUR with joint hypermobility. METHODS: To define the role of rare variants intenascin genes in the etiology of PVUR, we screened a cohort of patients with familial PVUR (FPVUR) and non-familial PVUR (NFPVUR) for rare missense variants inTNXB and the tenascin C gene (TNC) after excluding mutations in ROBO2 and SOX17. RESULTS: The screening procedure identified 134 individuals from 112 families with PVUR; two families with mutations in ROBO2 were excluded from further analysis. Rare missense variants in TNXB were found in the remaining 110 families, of which 5/55 (9%) families had FPVUR and 2/55 (4%) had NFPVUR. There were no differences in high-grade reflux or renal parenchymal scarring between patients with and without TNXB variants. All patients with TNXB rare variants who were tested exhibited joint hypermobility. Overall we were able to identify causes of FPVUR in 7/57 (12%) families (9% in TNXB and 3% in ROBO2). CONCLUSIONS: In conclusion, the identification of a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts.
Authors: S A Feather; S Malcolm; A S Woolf; V Wright; D Blaydon; C J Reid; F A Flinter; W Proesmans; K Devriendt; J Carter; P Warwicker; T H Goodship; J A Goodship Journal: Am J Hum Genet Date: 2000-03-17 Impact factor: 11.025
Authors: Rasheed A Gbadegesin; Patrick D Brophy; Adebowale Adeyemo; Gentzon Hall; Indra R Gupta; David Hains; Bartlomeij Bartkowiak; C Egla Rabinovich; Settara Chandrasekharappa; Alison Homstad; Katherine Westreich; Guanghong Wu; Yutao Liu; Danniele Holanda; Jason Clarke; Peter Lavin; Angelica Selim; Sara Miller; John S Wiener; Sherry S Ross; John Foreman; Charles Rotimi; Michelle P Winn Journal: J Am Soc Nephrol Date: 2013-04-25 Impact factor: 10.121
Authors: Daw-Yang Hwang; Gabriel C Dworschak; Stefan Kohl; Pawaree Saisawat; Asaf Vivante; Alina C Hilger; Heiko M Reutter; Neveen A Soliman; Radovan Bogdanovic; Elijah O Kehinde; Velibor Tasic; Friedhelm Hildebrandt Journal: Kidney Int Date: 2014-01-15 Impact factor: 10.612