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Lookup NU author(s): Dr Miranda Splitt
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We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six newde novo missense diagnoses in TBL1XR1 fromthe Deciphering Developmental Disorders study, together with population variation data, we show that the beta-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely delayed language development, often accompanied by intellectual disability, autism, dysmorphology and gastrointestinal problems. Amino acids affected by likely pathogenic missense mutations are either crucial for the stability of the fold, forming part of a highly conserved symmetrically repeating hydrogen-bonded tetrad, or located at the top face of the beta-propeller, where 'hotspot' residues affect the binding of beta-catenin to the TBLR1 protein. In contrast, those altered by population variation are significantly less likely to be spatially clustered towards the top face or to be at buried or highly conserved residues. This result is useful not only for interpreting benign and pathogenic missense variants in this gene, but also in other WD40 domains, many of which are associated with disease.
Author(s): Laskowski RA, Tyagi N, Johnson D, Joss S, Kinning E, McWilliam C, Splitt M, Thornton JM, Firth HV, Wright CF, DDD Study
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 2016
Volume: 25
Issue: 5
Pages: 927-935
Print publication date: 01/03/2016
Online publication date: 05/01/2016
Acceptance date: 22/12/2015
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/hmg/ddv625
DOI: 10.1093/hmg/ddv625
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