iPhemap: an atlas of phenotype to genotype relationships of human iPSC models of neurological diseases

Abstract

Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. Here, we report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We find heterogeneity in current research practices and a reporting bias toward certain diseases. Moreover, we identified 663 CNS cell‐derived phenotypes from 243 patients and 214 controls, which varied by mutation type and developmental stage in vitro. We clustered these phenotypes into a taxonomy and characterized these phenotype–genotype relationships to generate a phenogenetic map that revealed novel correlations among previously unrelated genes. We also find that alterations in patient‐derived molecular profiles associated with cellular phenotypes, and dysregulated genes show predominant expression in brain regions with pathology. Last, we developed the iPS cell phenogenetic map project atlas (iPhemap), an open submission, online database to continually catalog disease phenotypes. Overall, our findings offer new insights into the phenogenetics of iPSC‐derived models while our web tool provides a platform for researchers to query and deposit phenotypic information of neurological diseases.

Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium Authors

“…7 Though advances are increasingly encouraging, there is still considerable heterogeneity in research practices. 4,35 This is especially evident in genetic QC, which in recent years only has received systematic attention in large cohorts. 5,9 Despite a wealth of available experience from pioneering genetic fields regarding rare diseases or cancer genetics, the community has not yet agreed upon common minimal standards for an iPSC line to be acceptable as a model and to be safe for therapeutic use.…”

Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation

“…Although there are genetically diverse lines to reflect heterogeneity found within the human population, all control lines are potentially compromised by genetic variants that may predispose to a phenotype or mask it (DeBoever et al, 2017; Hollingsworth et al, 2017). To date, disease modeling has focused on penetrant monogenic disorders that may be relatively unaffected by the presence of concurrent variants (Cheung et al, 2011; Lan et al, 2013; Li et al, 2013).…”

Convergent molecular defects underpin diverse neurodegenerative diseases

“…There are now numerous studies in iPSC-based models with considerable heterogeneity in research practices and extent of maturity of such iPSC-derived cells. Nevertheless, recent attempts to generate a phenogenetic on-line database (iPhemap) to catalogue disease phenotypes will greatly assist our search for and understanding of emerging common mechanisms across NDD 113. Phenotypic characterisation of iPSC-derived neurons from patients with monogenic forms of NDD has reinforced the notion that neurons exhibit similar cellular defects.…”