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Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability
- Source :
- PLoS ONE, Vol 16, Iss 8, p e0256181 (2021), PLoS ONE, PLoS ONE, Public Library of Science, 2021, 16 (8), pp.e0256181. ⟨10.1371/journal.pone.0256181⟩, Bengani, H, Grozeva, D, Moyon, L, Bhatia, S, Louros, S R, Hope, J, Jackson, A, Prendergast, J G, Owen, L J, Naville, M, Rainger, J, Grimes, G, Halachev, M, Murphy, L C, Spasic-Boskovic, O, van Heyningen, V, Kind, P, Abbott, C M, Osterweil, E, Raymond, F L, Roest Crollius, H & FitzPatrick, D R 2021, ' Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability ', PLoS ONE, vol. 16, no. 8, e0256181 . https://doi.org/10.1371/journal.pone.0256181
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- Funder: BBSRC studentship<br />Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.
- Subjects :
- Male
Embryology
Embryo, Nonmammalian
X-linked intellectual disability
medicine.disease_cause
Hippocampus
Midbrain
Animals, Genetically Modified
Cohort Studies
Fragile X Mental Retardation Protein
Mice
0302 clinical medicine
Gene Frequency
Genes, X-Linked
Medicine and Health Sciences
Exome
Regulatory Elements, Transcriptional
Zebrafish
X chromosome
Genetics
0303 health sciences
education.field_of_study
Mutation
Mammalian Genomics
Multidisciplinary
Eukaryota
Brain
Chromosome Mapping
Tenascin
Animal Models
Genomics
Pedigree
Phenotype
Experimental Organism Systems
Osteichthyes
Vertebrates
Medicine
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Anatomy
Brainstem
Research Article
Genotype
Science
Population
Mouse Models
Nerve Tissue Proteins
Biology
Research and Analysis Methods
03 medical and health sciences
Model Organisms
medicine
Animals
Humans
Allele
education
Gene
Alleles
030304 developmental biology
Whole genome sequencing
[SDV.GEN]Life Sciences [q-bio]/Genetics
Genome, Human
Embryos
Organisms
Biology and Life Sciences
medicine.disease
FMR1
Disease Models, Animal
Fish
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Animal Genomics
Genetic Loci
Animal Studies
Mental Retardation, X-Linked
Zoology
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 16
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....689bedb7f80332ef6f820a6237c9dcc3