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 miss

SUBMITTER: Laskowski RA 

PROVIDER: S-EPMC4754046 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature