Reclassifying inconclusive diagnosis after newborn screening for cystic fibrosis. Moving forward |
| |
| Affiliation: | 1. INSERM U1151, Institut Necker Enfants Malades, Université de Paris, 149 rue de Sévres, Paris 75015, France;2. Université de Paris, Paris, France;3. PhyMedExp, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France;4. CHU de Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France;5. Cystic Fibrosis Department, Institute of Mother and Child, Warsaw, Poland;6. Université de Montpellier, Montpellier, France;7. Laboratoire de Génétique et Biologie Moléculaires, Hôpital Cochin, APHP Centre, Université de Paris, Paris, France;8. Centre de Référence Maladies Rares, Mucoviscidose et maladies apparentées, Hôpital Necker Enfants Malades, Paris, France;9. European Reference Network-Lung, France;1. Dept of Respiratory Medicine, The Children''s Hospital at Westmead, Respiratory Medicine, Locked Bag 4001, Westmead, Sydney, Australia;2. Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Australia;3. Translational Medicine, Division of Respiratory Medicine, Sellers Chair of Cystic Fibrosis, Hospital for Sick Children, 555 University Avenue, Toronto Ontario M5G 1 × 8, Canada;4. Dept of Community Health and Epidemiology, Dalhousie University, Halifax, Canada;5. National Heart and Lung Institute, Imperial College London, United Kingdom;6. Royal Brompton Hospital, Guys & St Thomas’ NHS Foundation Trust, London, United Kingdom;7. University of Toronto, Toronto, Canada;1. Sheffield Adult CF Center, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Herries Road, Sheffield S5 7AU, UK;2. School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK;1. Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA;2. Department of Respirology, St Michael''s Hospital, University of Toronto, Toronto, Ontario, Canada;3. Department of Pediatrics, University of Washington, Seattle, WA, USA;4. Seattle Children''s Research Institute, Seattle, WA, USA;1. Division of Thoracic Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States;2. Department of Medicine, Pulmonary, Allergy, and Critical Care Medicine Division, University of Pittsburgh, Pittsburgh, PA, United States;1. Louvain Center for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique;2. Cystic Fibrosis Center, Belgium;3. Medicinal Chemistry Research Lab, Louvain Drug Research Institute;4. Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute;5. Université catholique de Louvain (UCLouvain), Brussels, Belgium;6. Katholieke Universiteit Leuven (UZLeuven), Leuven, Belgium |
| |
| Abstract: | BackgroundNewborn screening for Cystic Fibrosis (CF) is associated with situations where the diagnosis of CF or CFTR related disorders (CFTR-RD) cannot be clearly ruled out.Materials/patients and methodsWe report a case series of 23 children with unconclusive diagnosis after newborn screening for CF and a mean follow-up of 7.7 years (4–13). Comprehensive investigations including whole CFTR gene sequencing, in vivo intestinal current measurement (ICM), nasal potential difference (NPD), and in vitro functional studies of variants of unknown significance, helped to reclassify the patients.ResultsExtensive genetic testing identified, in trans with a CF causing mutation, variants with varying clinical consequences and 3 variants of unknown significance (VUS). Eighteen deep intronic variants were identified by deep resequencing of the whole CFTR gene in 13 patients and were finally considered as non-pathogenic. All patients had normal CFTR dependent chloride transport in ICM. NPD differentiated 3 different profiles: CF-like tracings qualifying the patients as CF, such as F508del/D1152H patients; normal responses, suggesting an extremely low likelihood of developing a CFTR-RD such as F508del/TG11T5 patients; partial CFTR dysfunction above 20% of the normal, highlighting a remaining risk of developing CFTR-RD such as F508del/F1052V patients. The 3 VUS were reclassified as variant with defective maturation (D537N), defective expression (T582I) or with no clinical consequence (M952T).ConclusionThis study demonstrates the usefulness of combining genetic and functional investigations to assess the possibility of evolving to CF or CFTR-RD in babies with inconclusive diagnosis at neonatal screening. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
