Assessment of predicted enzymatic activity of α‐N‐acetylglucosaminidase variants of unknown significance for CAGI 2016. Issue 9 (13th September 2019)

• Record Type: Journal Article
• Authors: Clark, Wyatt T.; Kasak, Laura; Bakolitsa, Constantina; Hu, Zhiqiang; Andreoletti, Gaia; Babbi, Giulia; Bromberg, Yana; Casadio, Rita; Dunbrack, Roland; Folkman, Lukas; Ford, Colby T.; Jones, David; Katsonis, Panagiotis; Kundu, Kunal; Lichtarge, Olivier; Martelli, Pier L.; Mooney, Sean D.; Nodzak, Conor; Pal, Lipika R.; Radivojac, Predrag; Savojardo, Castrense; Shi, Xinghua; Zhou, Yaoqi; Uppal, Aneeta; Xu, Qifang; Yin, Yizhou; Pejaver, Vikas; Wang, Meng; Wei, Liping; Moult, John; Yu, Guoying Karen; Brenner, Steven E.; LeBowitz, Jonathan H.;
• Editors: Moult, John; Brenner, Steven E.
• Other Names: Karchin Rachel guestEditor.; Pal Lipika R. specialEditor.
• Is Part Of: Human mutation. Volume 40:Issue 9(2019)
• Page Start: 1519
• Page End: 1529
• Publication Date: 2019-09-13
• Subjects: CAGI -- critical assessment -- enzymatic activity -- machine learning -- Sanfilippo syndrome -- variants of unknown significance -- α‐N‐acetylglucosaminidase, NAGLU; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23875
• Languages: English
• ISSNs: 1059-7794

Abstract

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 .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.