Clara D M van Karnebeek1,2,3,4, Madhuri R Hegde5,6, Joseph J Shen7, Saskia B Wortmann8,1, Lonneke de Boer1, Leo A J Kluijtmans9, Marleen C D G Huigen9, Johannes Koch8, Stephanie Ross5, Christin D Collins5, Robin van der Lee2. 1. Radboud Centre for Mitochondrial Medicine, Department of Paediatrics, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands. 2. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. 3. Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada. 4. Department of Paediatrics, Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, The Netherlands. 5. PerkinElmer Genomics, Duluth, GA, USA. 6. Department of Applied Biology, Georgia Institute of Technology, Atlanta, GA, USA. 7. Division of Genetics, Department of Pediatrics, UCSF Fresno, Fresno, CA, USA. jojshen@ucdavis.edu. 8. University Children's Hospital, PMU Salzburg, Salzburg, Austria. 9. Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, The Netherlands.
Abstract
PURPOSE: The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity. METHODS: Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized. RESULTS: Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families. CONCLUSION: We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.
PURPOSE: The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity. METHODS: Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized. RESULTS: Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families. CONCLUSION: We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.
Authors: Eva M M Hoytema van Konijnenburg; Saskia B Wortmann; Marina J Koelewijn; Laura A Tseng; Roderick Houben; Sylvia Stöckler-Ipsiroglu; Carlos R Ferreira; Clara D M van Karnebeek Journal: Orphanet J Rare Dis Date: 2021-04-12 Impact factor: 4.123
Authors: Ingeborg Hauth; Hans R Waterham; Ronald J A Wanders; Saskia N van der Crabben; Clara D M van Karnebeek Journal: Cold Spring Harb Mol Case Stud Date: 2022-03-24
Authors: Saskia B Wortmann; Machteld M Oud; Mariëlle Alders; Karlien L M Coene; Saskia N van der Crabben; René G Feichtinger; Alejandro Garanto; Alex Hoischen; Mirjam Langeveld; Dirk Lefeber; Johannes A Mayr; Charlotte W Ockeloen; Holger Prokisch; Richard Rodenburg; Hans R Waterham; Ron A Wevers; Bart P C van de Warrenburg; Michel A A P Willemsen; Nicole I Wolf; Lisenka E L M Vissers; Clara D M van Karnebeek Journal: J Inherit Metab Dis Date: 2022-05-22 Impact factor: 4.750