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Published on: December 20, 2017
Moonlighting newborn screening markers: the incidental discovery of a second-tier test for Pompe disease
Silvia Tortorelli1, Jason S Eckerman2, Joseph J Orsini3
1Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. Tortorelli.Silvia@mayo.edu.
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.
