Assessment of predicted enzymatic activity of alpha-N-acetylglucosaminidase (NAGLU) variants of unknown significance for CAGI 2016.

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TitleAssessment of predicted enzymatic activity of alpha-N-acetylglucosaminidase (NAGLU) variants of unknown significance for CAGI 2016.
Publication TypeJournal Article
Year of Publication2019
AuthorsClark, WT, Kasak, L, Bakolitsa, C, Hu, Z, Andreoletti, G, Babbi, G, Bromberg, Y, Casadio, R, Dunbrack, R, Folkman, L, Ford, CT, Jones, D, Katsonis, P, Kundu, K, Lichtarge, O, Martelli, PLuigi, Mooney, SD, Nodzak, C, Pal, LR, Radivojac, P, Savojardo, C, Shi, X, Zhou, Y, Uppal, A, Xu, Q, Yin, Y, Pejaver, V, Wang, M, Wei, L, Moult, J, G Yu, K, Brenner, SE, LeBowitz, JH
JournalHum Mutat
Date Published2019 Jul 24
ISSN1098-1004
Abstract

The NAGLU challenge of the fourth edition of the Critical Assessment of Genome Interpretation experiment (CAGI4) in 2016, invited participants to predict the impact of variants of unknown significance (VUS) on the enzymatic activity of the lysosomal hydrolase α-N-acetylglucosaminidase (NAGLU). Deficiencies in NAGLU activity lead to a rare, monogenic, recessive lysosomal storage disorder, Sanfilippo syndrome type B (MPS type IIIB). This challenge attracted 17 submissions from 10 groups. We observed that top models were able to predict the impact of missense mutations on enzymatic activity with Pearson's correlation coefficients of up to 0.61. We also observed that top methods were significantly more correlated with each other than they were with observed enzymatic activity values, which we believe speaks to the importance of sequence conservation across the different methods. Improved functional predictions on the VUS will help population scale analysis of disease epidemiology and rare variant association analysis. This article is protected by copyright. All rights reserved.

DOI10.1002/humu.23875
Alternate JournalHum. Mutat.
PubMed ID31342580