title: Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California.
abstract: Of the 2007 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, 202 have been assigned disease liability. California's racially diverse population, along with CFTR sequencing as part of newborn screening model, provides the opportunity to examine the phenotypes of children with uncategorized mutations to help inform disease liability and penetrance.
  
  
  
  We conducted a retrospective cohort study based on children screened from 2007 to 2011 and followed for two to six years. Newborns that screened positive were divided into three genotype groups: those with two CF-causing mutations (CF-C); those with one mutation of varying clinic consequence (VCC); and those with one mutation of unknown disease liability (Unknown). Sweat chloride tests, pancreatic sufficiency status, and Pseudomonas aeruginosa colonization were compared.
  
  
  
  Children with two CF-causing mutations had a classical CF phenotype, while 5% of VCC (4/78) and 11% of Unknown (27/244) met diagnostic criteria of CF. Children carrying Unknown mutations 2215insG with D836Y, and T1036N had early and classical CF phenotype, while others carrying 1525-42G>A, L320V, L967S, R170H, and 296+28A>G had a benign clinical presentation, suggesting that these are non-CF causing.
  
  
  
  While most infants with VCC and Unknown CFTR mutations do not meet diagnostic criteria for CF, a small proportion do. These findings highlight the range of genotypes and phenotypes in the first few years of life following CF newborn screening when CFTR sequencing is performed.
authors.affiliation: Department of Pediatrics, Division of Pediatric Pulmonology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Danieli B
authors.initials: DB
authors.lastname: Salinas
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine and McKusick-Nathans Institute of Medical Genetics, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Sosnay
authors.affiliation: Department of Biostatistics, Southern California Clinical and Translational Science Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Colleen
authors.initials: C
authors.lastname: Azen
authors.affiliation: The Sequoia Foundation, La Jolla, California, United States of America.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Young
authors.affiliation: McKusick-Nathans Institute of Medical Genetics, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Raraigh
authors.affiliation: Department of Pediatrics, Division of Pediatric Pulmonology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Keens
authors.affiliation: Division of Environmental and Occupational Disease Control, Environmental Health Investigations Branch, Environmental Epidemiology Section, California Department of Public Health, Richmond, California, United States of America.
authors.forename: Martin
authors.initials: M
authors.lastname: Kharrazi
mesh_terms: D002140:California; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator