Annie Dupuis1,2, Katherine Keenan3, Chee Y Ooi4,5, Ruslan Dorfman6, Marci K Sontag7, Lutz Naehrlich8, Carlo Castellani9, Lisa J Strug2,10, Johanna M Rommens10,11, Tanja Gonska2,12. 1. Clinical Research Services, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada. 2. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. 3. Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada. 4. Discipline of Paediatrics, School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, Australia. 5. Department of Gastroenterology, Sydney Children's Hospital Randwick, New South Wales, Australia. 6. GeneYouIn Inc., Toronto, Ontario, Canada. 7. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA. 8. Department of Pediatrics, Justus-Liebig-University Giessen, Giessen, Germany. 9. Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. 10. Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children and Division of Biostatistics. 11. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. 12. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
Abstract
RATIONALE: Meconium ileus (MI) is a perinatal complication in cystic fibrosis (CF), which is only minimally influenced by environmental factors. We derived and examined MI prevalence (MIP) scores to assess CFTR phenotype-phenotype correlation for severe mutations. METHOD: MIP scores were established using a Canadian CF population (n = 2,492) as estimates of the proportion of patients with MI among all patients carrying the same CFTR mutation, focusing on patients with p.F508del as the second allele. Comparisons were made to the registries from the US CF Foundation (n = 43,432), Italy (Veneto/Trentino/Alto Adige regions) (n = 1,788), and Germany (n = 3,596). RESULTS: The prevalence of MI varied among the different registries (13-21%). MI was predominantly prevalent in patients with pancreatic insufficiency carrying "severe" CFTR mutations. In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Higher MIP scores were associated with more severe clinical phenotypes, such as a lower forced expiratory volume in 1 second (P = 0.01) and body mass index z score (P = 0.04). CONCLUSIONS: MIP scores can be used to rank CFTR mutations according to their clinical severity and provide a means to expand delineation of CF phenotypes.Genet Med 18 4, 333-340.
RATIONALE: Meconium ileus (MI) is a perinatal complication in cystic fibrosis (CF), which is only minimally influenced by environmental factors. We derived and examined MI prevalence (MIP) scores to assess CFTR phenotype-phenotype correlation for severe mutations. METHOD: MIP scores were established using a Canadian CF population (n = 2,492) as estimates of the proportion of patients with MI among all patients carrying the same CFTR mutation, focusing on patients with p.F508del as the second allele. Comparisons were made to the registries from the US CF Foundation (n = 43,432), Italy (Veneto/Trentino/Alto Adige regions) (n = 1,788), and Germany (n = 3,596). RESULTS: The prevalence of MI varied among the different registries (13-21%). MI was predominantly prevalent in patients with pancreatic insufficiency carrying "severe" CFTR mutations. In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Higher MIP scores were associated with more severe clinical phenotypes, such as a lower forced expiratory volume in 1 second (P = 0.01) and body mass index z score (P = 0.04). CONCLUSIONS: MIP scores can be used to rank CFTR mutations according to their clinical severity and provide a means to expand delineation of CF phenotypes.Genet Med 18 4, 333-340.
Authors: Teresa R Gray; Tamsin Kelly; Linda L LaGasse; Lynne M Smith; Chris Derauf; Penny Grant; Rizwan Shah; Amelia Arria; William Haning; Sheri Della Grotta; Arthur Strauss; Barry M Lester; Marilyn A Huestis Journal: Clin Chem Date: 2010-02-25 Impact factor: 8.327
Authors: J Zielenski; T M Fujiwara; D Markiewicz; A J Paradis; A I Anacleto; B Richards; R H Schwartz; K W Klinger; L C Tsui; K Morgan Journal: Am J Hum Genet Date: 1993-03 Impact factor: 11.025
Authors: T Shoshani; A Augarten; E Gazit; N Bashan; Y Yahav; Y Rivlin; A Tal; H Seret; L Yaar; E Kerem Journal: Am J Hum Genet Date: 1992-01 Impact factor: 11.025
Authors: A Hamosh; T M King; B J Rosenstein; M Corey; H Levison; P Durie; L C Tsui; I McIntosh; M Keston; D J Brock Journal: Am J Hum Genet Date: 1992-08 Impact factor: 11.025
Authors: Lindsay B Henderson; Vishal K Doshi; Scott M Blackman; Kathleen M Naughton; Rhonda G Pace; Jackob Moskovitz; Michael R Knowles; Peter R Durie; Mitchell L Drumm; Garry R Cutting Journal: PLoS Genet Date: 2012-03-15 Impact factor: 5.917
Authors: Kavisha Arora; Yunjie Huang; Kyushik Mun; Sunitha Yarlagadda; Nambirajan Sundaram; Marco M Kessler; Gerhard Hannig; Caroline B Kurtz; Inmaculada Silos-Santiago; Michael Helmrath; Joseph J Palermo; John P Clancy; Kris A Steinbrecher; Anjaparavanda P Naren Journal: JCI Insight Date: 2017-10-05
Authors: Scott C Bell; Jochen G Mainz; Gordon MacGregor; Susan Madge; Julie Macey; Moshe Fridman; Ellison D Suthoff; Siva Narayanan; Nils Kinnman Journal: BMC Pulm Med Date: 2019-08-13 Impact factor: 3.317
Authors: Jiafen Gong; Fan Wang; Bowei Xiao; Naim Panjwani; Fan Lin; Katherine Keenan; Julie Avolio; Mohsen Esmaeili; Lin Zhang; Gengming He; David Soave; Scott Mastromatteo; Zeynep Baskurt; Sangook Kim; Wanda K O'Neal; Deepika Polineni; Scott M Blackman; Harriet Corvol; Garry R Cutting; Mitchell Drumm; Michael R Knowles; Johanna M Rommens; Lei Sun; Lisa J Strug Journal: PLoS Genet Date: 2019-02-26 Impact factor: 5.917