title: Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain.
abstract: 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 new de novo missense diagnoses in TBL1XR1 from the Deciphering Developmental Disorders study, together with population variation data, we show that the β-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 β-propeller, where 'hotspot' residues affect the binding of β-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.
authors.affiliation: European Bioinformatics Institute (EMBL-EBI) and.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Laskowski
authors.affiliation: European Bioinformatics Institute (EMBL-EBI) and.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Tyagi
authors.affiliation: Sheffield Regional Genetics Services, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Johnson
authors.affiliation: West of Scotland Genetic Services, Level 1, Laboratory Medicine Building, South Glasgow University Hospital, 1345 Govan Road, Glasgow G51 4TF, UK.
authors.forename: Shelagh
authors.initials: S
authors.lastname: Joss
authors.affiliation: West of Scotland Genetic Services, Level 1, Laboratory Medicine Building, South Glasgow University Hospital, 1345 Govan Road, Glasgow G51 4TF, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Kinning
authors.affiliation: Human Genetics, Ninewells Hospital, Dundee DD1 9SY, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: McWilliam
authors.affiliation: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK and.
authors.forename: Miranda
authors.initials: M
authors.lastname: Splitt
authors.affiliation: European Bioinformatics Institute (EMBL-EBI) and.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Thornton
authors.affiliation: East Anglian Medical Genetics Service, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge CB2 0QQ, UK.
authors.forename: Helen V
authors.initials: HV
authors.lastname: Firth
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK, caroline.wright@sanger.ac.uk.
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Wright
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D018740:Genetic Heterogeneity; D005828:Genetics, Population; D006801:Humans; D006860:Hydrogen Bonding; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D051176:beta Catenin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C473691:TBL1XR1 protein, human; D051176:beta Catenin