ArticleStem cell research & therapy2022
CRISPR single base editing, neuronal disease modelling and functional genomics for genetic variant analysis: pipeline validation using Kleefstra syndrome EHMT1 haploinsufficiency.
Article in Stem cell research & therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 24 citations in OpenAlex.
- A precision medicine approach to interpret a GATA4 genetic variant in a paediatric patient with congenital heart disease.Human genomics · 2026Article
- Histone acetylation and methylation in rare diseases: from molecular mechanisms to clinical presentations.Frontiers in cell and developmental biology · 2026Review
- Functional characterization of the MED12 p.Arg1138Trp variant in females: implications for neural development and disease mechanism.Molecular medicine (Cambridge, Mass.) · 2025Article
- Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling.Molecular autism · 2024Article
- Establishment of human pluripotent stem cell-derived cortical neurosphere model to study pathomechanisms and chemical toxicity in Kleefstra syndrome.Scientific reports · 2024Article
- Leaving no patient behind! Expert recommendation in the use of innovative technologies for diagnosing rare diseases.Orphanet journal of rare diseases · 2024Review
- CRISPR-Cas9-generated PTCHD1 2489T>G stem cells recapitulate patient phenotype when undergoing neural induction.HGG advances · 2024Article
- Gene editing and cardiac disease modelling for the interpretation of genetic variants of uncertain significance in congenital heart disease.Stem cell research & therapy · 2023Article
- Application of CRISPR/Cas9 Technology in Cancer Treatment: A Future Direction.Current oncology (Toronto, Ont.) · 2023Review
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundOver 400 million people worldwide are living with a rare disease. Next Generation Sequencing (NGS) identifies potential disease causative genetic variants. However, many are identified as variants of uncertain significance (VUS) and require functional laboratory validation to determine pathogenicity, and this creates major diagnostic delays.
methodsIn this study we test a rapid genetic variant assessment pipeline using CRISPR homology directed repair to introduce single nucleotide variants into inducible pluripotent stem cells (iPSCs), followed by neuronal disease modelling, and functional genomics on amplicon and RNA sequencing, to determine cellular changes to support patient diagnosis and identify disease mechanism.
resultsAs proof-of-principle, we investigated an EHMT1 (Euchromatin histone methyltransferase 1; EHMT1 c.3430C > T; p.Gln1144*) genetic variant pathogenic for Kleefstra syndrome and determined changes in gene expression during neuronal progenitor cell differentiation. This pipeline rapidly identified Kleefstra syndrome in genetic variant cells compared to healthy cells, and revealed novel findings potentially implicating the key transcription factors REST and SP1 in disease pathogenesis.
conclusionThe study pipeline is a rapid, robust method for genetic variant assessment that will support rare diseases patient diagnosis. The results also provide valuable information on genome wide perturbations key to disease mechanism that can be targeted for drug treatments.
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