Assessing PAH Genotype Severity Using Assigned Value (AV Sample Clauses

Assessing PAH Genotype Severity Using Assigned Value (AV. Sum‌ PAH genotype severity was assessed using the assigned valued (AV) sum approach developed by Guldberg et al [186]. The method was created by evaluating nearly 300 functionally hemizygous patients with PKU and using the patients’ phenotypic severity to classifying a total of 105 different mutations. Each mutation was given an AV of 1, 2, 4, or 8. A lower mutation AV corresponds to a more severe phenotype. Mutations with an AV of 1 are considered particularly severe in nature, with many classified as putative null mutations. Mutations with AV >1 are associated with moderate or mild phenotypes, suggesting that the mutation retains some functionality. To assess the severity of a patient’s genotype, both mutations’ AVs are added together (the “AV sum”). AV sums range from 2 to 16, again with a lower number indicating a more severe phenotype. Some minor modifications to the AV sum approach were necessary for our analysis. First, there were certain mutations which had been assigned to multiple AVs due to a wide range of clinical phenotypes observed in the original analysis. In those instances, we only used the mutation AV most frequently designated by Guldberg et al (see Appendix in ref [186]). To expand our ability to give a patient an AV sum, decidedly severe mutations not previously evaluated in the AV sum analysis—such as large deletions, frame shift mutations, and disruptions of canonical splice site motifs—were given a mutation AV of 1. Finally, since not all mutations identified in our clinic population had a designated mutation AV, some patients were given an “indefinite AV sum” (e.g. ≥2, ≥3, ≥4, etc). The indefinite AV sum is, at minimum, one greater than the AV for the characterized mutation.