Tony Yao1,2, Khalil Udwan1,2, Rohan John3, Akanchaya Rana1,2,4, Amirreza Haghighi1, Lizhen Xu5, Saidah Hack1,2, Heather N Reich1,2,4,6, Michelle Adrienne Hladunewich7, Daniel C Cattran1,2,4,6, Andrew D Paterson4,6,8,9, York Pei1,2,4,6, Moumita Barua10,2,4,6. 1. Division of Nephrology and. 2. Toronto General Hospital Research Institute, Toronto General Hospital, Toronto, Canada. 3. Department of Pathology, University Health Network, Toronto, Canada. 4. Institute of Medical Sciences. 5. The Centre for Applied Genomics and. 6. Department of Medicine, and. 7. Division of Nephrology, Sunnybrook Health Sciences Center, Toronto, Canada. 8. Genetics and Genome Biology, Research Institute at Hospital for Sick Children, Toronto, Canada; and. 9. Division of Epidemiology and Biostatistics, Dalla Lana School of Public Health, Toronto, Ontario, Canada. 10. Division of Nephrology and moumita.barua@uhn.ca.
Abstract
BACKGROUND AND OBJECTIVES: FSGS and nephrotic syndrome studies have shown that single gene causes are more likely to be found in pediatric cases than adults. Consequently, many studies have examined limited gene panels in largely pediatric cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole-exome sequencing was performed in adults with FSGS diagnosed between 1976 and 2017 in the Toronto GN Registry. An expanded panel of 109 genes linked to FSGS, glomerular basement membrane abnormalities, as well as causes of pediatric ESKD including congenital abnormalities of the kidney and urinary tract (CAKUT) and nephronophthisis, were examined. RESULTS: The cohort was composed of 193 individuals from 179 families. Nearly half (49%) developed ESKD at a mean age of 47±17 years. The genetic diagnostic rate was 11%. Of definitely pathogenic variants, 55% were in COL4A (A3/A4/A5), 40% were in podocyte genes, and 5% were in CAKUT genes. Many, but not all individuals with COL4A definitely pathogenic variants had some evidence of glomerular basement membrane abnormalities. The estimated mean survival/age of kidney failure for individuals with COL4A definitely pathogenic variants was 58 years (95% confidence interval, 49 to 69), far later than what has been reported in the literature. Likely pathogenic variants were identified in an additional 9% of the cohort, with most in COL4A. Correlation with glomerular basement membrane morphology suggested a causal role for at least some of these likely pathogenic variants. CONCLUSIONS: Even with an expanded gene panel, we find that COL4A disorders are the leading monogenic cause in adults diagnosed with FSGS. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_01_15_CJASNPodcast_19_02_.mp3.
BACKGROUND AND OBJECTIVES: FSGS and nephrotic syndrome studies have shown that single gene causes are more likely to be found in pediatric cases than adults. Consequently, many studies have examined limited gene panels in largely pediatric cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole-exome sequencing was performed in adults with FSGS diagnosed between 1976 and 2017 in the Toronto GN Registry. An expanded panel of 109 genes linked to FSGS, glomerular basement membrane abnormalities, as well as causes of pediatric ESKD including congenital abnormalities of the kidney and urinary tract (CAKUT) and nephronophthisis, were examined. RESULTS: The cohort was composed of 193 individuals from 179 families. Nearly half (49%) developed ESKD at a mean age of 47±17 years. The genetic diagnostic rate was 11%. Of definitely pathogenic variants, 55% were in COL4A (A3/A4/A5), 40% were in podocyte genes, and 5% were in CAKUT genes. Many, but not all individuals with COL4A definitely pathogenic variants had some evidence of glomerular basement membrane abnormalities. The estimated mean survival/age of kidney failure for individuals with COL4A definitely pathogenic variants was 58 years (95% confidence interval, 49 to 69), far later than what has been reported in the literature. Likely pathogenic variants were identified in an additional 9% of the cohort, with most in COL4A. Correlation with glomerular basement membrane morphology suggested a causal role for at least some of these likely pathogenic variants. CONCLUSIONS: Even with an expanded gene panel, we find that COL4A disorders are the leading monogenic cause in adults diagnosed with FSGS. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_01_15_CJASNPodcast_19_02_.mp3.
Authors: Aaron McKenna; Matthew Hanna; Eric Banks; Andrey Sivachenko; Kristian Cibulskis; Andrew Kernytsky; Kiran Garimella; David Altshuler; Stacey Gabriel; Mark Daly; Mark A DePristo Journal: Genome Res Date: 2010-07-19 Impact factor: 9.043
Authors: Moumita Barua; Emilia Stellacci; Lorenzo Stella; Astrid Weins; Giulio Genovese; Valentina Muto; Viviana Caputo; Hakan R Toka; Victoria T Charoonratana; Marco Tartaglia; Martin R Pollak Journal: J Am Soc Nephrol Date: 2014-03-27 Impact factor: 10.121
Authors: David M Altshuler; Richard A Gibbs; Leena Peltonen; David M Altshuler; Richard A Gibbs; Leena Peltonen; Emmanouil Dermitzakis; Stephen F Schaffner; Fuli Yu; Leena Peltonen; Emmanouil Dermitzakis; Penelope E Bonnen; David M Altshuler; Richard A Gibbs; Paul I W de Bakker; Panos Deloukas; Stacey B Gabriel; Rhian Gwilliam; Sarah Hunt; Michael Inouye; Xiaoming Jia; Aarno Palotie; Melissa Parkin; Pamela Whittaker; Fuli Yu; Kyle Chang; Alicia Hawes; Lora R Lewis; Yanru Ren; David Wheeler; Richard A Gibbs; Donna Marie Muzny; Chris Barnes; Katayoon Darvishi; Matthew Hurles; Joshua M Korn; Kati Kristiansson; Charles Lee; Steven A McCarrol; James Nemesh; Emmanouil Dermitzakis; Alon Keinan; Stephen B Montgomery; Samuela Pollack; Alkes L Price; Nicole Soranzo; Penelope E Bonnen; Richard A Gibbs; Claudia Gonzaga-Jauregui; Alon Keinan; Alkes L Price; Fuli Yu; Verneri Anttila; Wendy Brodeur; Mark J Daly; Stephen Leslie; Gil McVean; Loukas Moutsianas; Huy Nguyen; Stephen F Schaffner; Qingrun Zhang; Mohammed J R Ghori; Ralph McGinnis; William McLaren; Samuela Pollack; Alkes L Price; Stephen F Schaffner; Fumihiko Takeuchi; Sharon R Grossman; Ilya Shlyakhter; Elizabeth B Hostetter; Pardis C Sabeti; Clement A Adebamowo; Morris W Foster; Deborah R Gordon; Julio Licinio; Maria Cristina Manca; Patricia A Marshall; Ichiro Matsuda; Duncan Ngare; Vivian Ota Wang; Deepa Reddy; Charles N Rotimi; Charmaine D Royal; Richard R Sharp; Changqing Zeng; Lisa D Brooks; Jean E McEwen Journal: Nature Date: 2010-09-02 Impact factor: 49.962
Authors: M Kestilä; U Lenkkeri; M Männikkö; J Lamerdin; P McCready; H Putaala; V Ruotsalainen; T Morita; M Nissinen; R Herva; C E Kashtan; L Peltonen; C Holmberg; A Olsen; K Tryggvason Journal: Mol Cell Date: 1998-03 Impact factor: 17.970
Authors: Elizabeth J Brown; Johannes S Schlöndorff; Daniel J Becker; Hiroyasu Tsukaguchi; Stephen J Tonna; Andrea L Uscinski; Henry N Higgs; Joel M Henderson; Martin R Pollak Journal: Nat Genet Date: 2009-12-20 Impact factor: 38.330
Authors: Susan L Murray; Anthony Dorman; Katherine A Benson; Dervla M Connaughton; Caragh P Stapleton; Neil K Fennelly; Claire Kennedy; Ciara A McDonnell; Kendrah Kidd; Sarah M Cormican; Louise A Ryan; Peter Lavin; Mark A Little; Anthony J Bleyer; Brendan Doyle; Gianpiero L Cavalleri; Friedhelm Hildebrandt; Peter J Conlon Journal: Am J Nephrol Date: 2019-12-10 Impact factor: 3.754
Authors: Glenn M Chertow; Gerald B Appel; Sharon Andreoli; Sripal Bangalore; Geoffrey A Block; Arlene B Chapman; Melanie P Chin; Keisha L Gibson; Angie Goldsberry; Kazumoto Iijima; Lesley A Inker; Bertrand Knebelmann; Laura H Mariani; Colin J Meyer; Kandai Nozu; Megan O'Grady; Arnold L Silva; Peter Stenvinkel; Roser Torra; Bradley A Warady; Pablo E Pergola Journal: Am J Nephrol Date: 2021-03-31 Impact factor: 3.754