Silvia Tortorelli1, Jason S Eckerman2, Joseph J Orsini3, Colleen Stevens3, Jeremy Hart4,5, Patricia L Hall6,7, John J Alexander6,7, Dimitar Gavrilov2, Devin Oglesbee2, Kimiyo Raymond2, Dietrich Matern2, Piero Rinaldo2. 1. Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. Tortorelli.Silvia@mayo.edu. 2. Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. 3. Laboratory of Human Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA. 4. Division of Laboratory Services, Kentucky Department for Public Health, Frankfort, Kentucky, USA. 5. Department of Pathology & Laboratory Medicine, University of Kentucky, Lexington, Kentucky, USA. 6. EGL Genetics, Tucker, Georgia, USA. 7. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
Abstract
PURPOSE: To describe a novel biochemical marker in dried blood spots suitable to improve the specificity of newborn screening for Pompe disease. METHODS: The new marker is a ratio calculated between the creatine/creatinine (Cre/Crn) ratio as the numerator and the activity of acid α-glucosidase (GAA) as the denominator. Using Collaborative Laboratory Integrated Reports (CLIR), the new marker was incorporated in a dual scatter plot that can achieve almost complete segregation between Pompe disease and false-positive cases. RESULTS: The (Cre/Crn)/GAA ratio was measured in residual dried blood spots of five Pompe cases and was found to be elevated (range 4.41-13.26; 99%ile of neonatal controls: 1.10). Verification was by analysis of 39 blinded specimens that included 10 controls, 24 samples with a definitive classification (16 Pompe, 8 false positives), and 5 with genotypes of uncertain significance. The CLIR tool showed 100% concordance of classification for the 24 known cases. Of the remaining five cases, three p.V222M homozygotes, a benign variant, were classified by CLIR as false positives; two with genotypes of unknown significance, one likely informative, were categorized as Pompe disease. CONCLUSION: The CLIR tool inclusive of the new ratio could have prevented at least 12 of 13 (92%) false-positive outcomes.
PURPOSE: To describe a novel biochemical marker in dried blood spots suitable to improve the specificity of newborn screening for Pompe disease. METHODS: The new marker is a ratio calculated between the creatine/creatinine (Cre/Crn) ratio as the numerator and the activity of acid α-glucosidase (GAA) as the denominator. Using Collaborative Laboratory Integrated Reports (CLIR), the new marker was incorporated in a dual scatter plot that can achieve almost complete segregation between Pompe disease and false-positive cases. RESULTS: The (Cre/Crn)/GAA ratio was measured in residual dried blood spots of five Pompe cases and was found to be elevated (range 4.41-13.26; 99%ile of neonatal controls: 1.10). Verification was by analysis of 39 blinded specimens that included 10 controls, 24 samples with a definitive classification (16 Pompe, 8 false positives), and 5 with genotypes of uncertain significance. The CLIR tool showed 100% concordance of classification for the 24 known cases. Of the remaining five cases, three p.V222M homozygotes, a benign variant, were classified by CLIR as false positives; two with genotypes of unknown significance, one likely informative, were categorized as Pompe disease. CONCLUSION: The CLIR tool inclusive of the new ratio could have prevented at least 12 of 13 (92%) false-positive outcomes.
Authors: Chris Stinton; Hannah Fraser; Julia Geppert; Rebecca Johnson; Martin Connock; Samantha Johnson; Aileen Clarke; Sian Taylor-Phillips Journal: Front Pediatr Date: 2021-03-19 Impact factor: 3.418
Authors: Alexander D Rowe; Stephanie D Stoway; Henrik Åhlman; Vaneet Arora; Michele Caggana; Anna Fornari; Arthur Hagar; Patricia L Hall; Gregg C Marquardt; Bobby J Miller; Christopher Nixon; Andrew P Norgan; Joseph J Orsini; Rolf D Pettersen; Amy L Piazza; Neil R Schubauer; Amy C Smith; Hao Tang; Norma P Tavakoli; Sainan Wei; Rolf H Zetterström; Robert J Currier; Lars Mørkrid; Piero Rinaldo Journal: Int J Neonatal Screen Date: 2021-04-23
Authors: Zaib Un Nisa Khan; Lena Jafri; Patricia L Hall; Matthew J Schultz; Sibtain Ahmed; Aysha Habib Khan; Hafsa Majid Journal: Ann Med Surg (Lond) Date: 2022-09-23