title: Gene networks underlying convergent and pleiotropic phenotypes in a large and systematically-phenotyped cohort with heterogeneous developmental disorders.
abstract: Readily-accessible and standardised capture of genotypic variation has revolutionised our understanding of the genetic contribution to disease. Unfortunately, the corresponding systematic capture of patient phenotypic variation needed to fully interpret the impact of genetic variation has lagged far behind. Exploiting deep and systematic phenotyping of a cohort of 197 patients presenting with heterogeneous developmental disorders and whose genomes harbour de novo CNVs, we systematically applied a range of commonly-used functional genomics approaches to identify the underlying molecular perturbations and their phenotypic impact. Grouping patients into 408 non-exclusive patient-phenotype groups, we identified a functional association amongst the genes disrupted in 209 (51%) groups. We find evidence for a significant number of molecular interactions amongst the association-contributing genes, including a single highly-interconnected network disrupted in 20% of patients with intellectual disability, and show using microcephaly how these molecular networks can be used as baits to identify additional members whose genes are variant in other patients with the same phenotype. Exploiting the systematic phenotyping of this cohort, we observe phenotypic concordance amongst patients whose variant genes contribute to the same functional association but note that (i) this relationship shows significant variation across the different approaches used to infer a commonly perturbed molecular pathway, and (ii) that the phenotypic similarities detected amongst patients who share the same inferred pathway perturbation result from these patients sharing many distinct phenotypes, rather than sharing a more specific phenotype, inferring that these pathways are best characterized by their pleiotropic effects.
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Tallulah
authors.initials: T
authors.lastname: Andrews
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Meader
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Vulto-van Silfhout
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Avigail
authors.initials: A
authors.lastname: Taylor
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Steinberg
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Jayne
authors.initials: J
authors.lastname: Hehir-Kwa
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: de Leeuw
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Caleb
authors.initials: C
authors.lastname: Webber
mesh_terms: D000818:Animals; D056915:DNA Copy Number Variations / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D056726:Genetic Association Studies; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps / Q000235:genetics*