Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data



Aitken, Stuart, Firth, Helen V, McRae, Jeremy, Halachev, Mihail, Kini, Usha, Parker, Michael J, Lees, Melissa M, Lachlan, Katherine, Sarkar, Ajoy, Joss, Shelagh
et al (show 273 more authors) (2019) Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data. The American Journal of Human Genetics, 105 (5). pp. 933-946.

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Abstract

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.

Item Type: Article
Uncontrolled Keywords: DDD Study, Humans, Dwarfism, Genetic Predisposition to Disease, Spectrin, Repressor Proteins, Bayes Theorem, Developmental Disabilities, Gene Frequency, Heterozygote, Phenotype, Mutation, Child, Female, Male, Exome, Exome Sequencing
Depositing User: Symplectic Admin
Date Deposited: 28 Nov 2019 10:16
Last Modified: 17 Mar 2024 23:13
DOI: 10.1016/j.ajhg.2019.09.015
Open Access URL: https://doi.org/10.1016/j.ajhg.2019.09.015
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3063828