@article{545ba7f90c9744a8a5328cac87b44963,
title = "Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation",
abstract = "Exome sequencing in diabetes presents a diagnostic challenge because depending on frequency, functional impact, and genomic and environmental contexts, HNF1A variants can cause maturity-onset diabetes of the young (MODY), increase type 2 diabetes risk, or be benign. A correct diagnosis matters as it informs on treatment, progression, and family risk. We describe a multi-dimensional functional dataset of 73 HNF1A missense variants identified in exomes of 12,940 individuals. Our aim was to develop an analytical framework for stratifying variants along the HNF1A phenotypic continuum to facilitate diagnostic interpretation. HNF1A variant function was determined by four different molecular assays. Structure of the multi-dimensional dataset was explored using principal component analysis, k-means, and hierarchical clustering. Weights for tissue-specific isoform expression and functional domain were integrated. Functionally annotated variant subgroups were used to re-evaluate genetic diagnoses in national MODY diagnostic registries. HNF1A variants demonstrated a range of behaviors across the assays. The structure of the multi-parametric data was shaped primarily by transactivation. Using unsupervised learning methods, we obtained high-resolution functional clusters of the variants that separated known causal MODY variants from benign and type 2 diabetes risk variants and led to reclassification of 4% and 9% of HNF1A variants identified in the UK and Norway MODY diagnostic registries, respectively. Our proof-of-principle analyses facilitated informative stratification of HNF1A variants along the continuum, allowing improved evaluation of clinical significance, management, and precision medicine in diabetes clinics. Transcriptional activity appears a superior readout supporting pursuit of transactivation-centric experimental designs for high-throughput functional screens.",
keywords = "association, classification, gene-mutations, mody, rare variants, GENE-MUTATIONS, MODY, RARE VARIANTS, CLASSIFICATION, ASSOCIATION",
author = "S. Althari and L.A. Najmi and A.J. Bennett and I. Aukrust and J.K. Rundle and K. Colclough and J. Molnes and A. Kaci and S. Nawaz and {van der Lugt}, T. and N. Hassanali and A. Mahajan and A. Molven and S. Ellard and M.I. McCarthy and L. Bjorkhaug and P.R. Njolstad and A.L. Gloyn",
note = "Funding Information: A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science. S.E. and M.I.M. are Wellcome Senior Investigators. This work was funded in Oxford by the Wellcome (095101 [A.L.G.], 200837 [A.L.G.], 098381 [M.I.M.], 106130 [A.L.G. M.I.M.], 203141 [A.L.G. M.I.M.], 203141 [M.I.M.]), Medical Research Council (MR/L020149/1 [M.I.M. A.L.G.]), European Union Horizon 2020 Programme (T2D Systems [A.L.G.]), and NIH (U01-DK105535; U01-DK085545 [M.I.M. A.L.G.]). The research was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC, [A.L.G. M.I.M.]). This work was funded in Bergen by grants from the European Research Council (#293574 [P.R.N.]), the Research Council of Norway (#240413/F20 [P.R.N.]), Stiftelsen Kristian Gerhard Jebsen (P.R.N.), the Novo Nordisk Fonden (#54741 [P.R.N.]), the Western Norway Health Authorities (#911745 [P.R.N.]), and the University of Bergen (I.A. L.A.N. P.R.N.). Funding Information: The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. M.I.M. has served on advisory panels for Pfizer, NovoNordisk, and Zoe Global, received honoraria from Merck, Pfizer, NovoNordisk, and Eli Lilly, and received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. A.L.G. reports grants from Wellcome Trust, grants from NIHR Oxford Biomedical Research Centre, grants from Horizon 2020, grants from NIDDK, and grants from MRC during the conduct of the study and personal fees from NovoNordisk and Merck outside the submitted work. Funding Information: A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science. S.E. and M.I.M. are Wellcome Senior Investigators. This work was funded in Oxford by the Wellcome ( 095101 [A.L.G.], 200837 [A.L.G.], 098381 [M.I.M.], 106130 [A.L.G., M.I.M.], 203141 [A.L.G., M.I.M.], 203141 [M.I.M.]), Medical Research Council ( MR/L020149/1 [M.I.M., A.L.G.]), European Union Horizon 2020 Programme (T2D Systems [A.L.G.]), and NIH ( U01-DK105535 ; U01-DK085545 [M.I.M., A.L.G.]). The research was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC, [A.L.G., M.I.M.]). This work was funded in Bergen by grants from the European Research Council (# 293574 [P.R.N.]), the Research Council of Norway (# 240413/F20 [P.R.N.]), Stiftelsen Kristian Gerhard Jebsen (P.R.N.), the Novo Nordisk Fonden (# 54741 [P.R.N.]), the Western Norway Health Authorities (# 911745 [P.R.N.]), and the University of Bergen (I.A., L.A.N., P.R.N.). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = oct,
day = "1",
doi = "10.1016/j.ajhg.2020.08.016",
language = "English",
volume = "107",
pages = "670--682",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",
}