PUBLICATION
Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability
- Authors
- 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.
- ID
- ZDB-PUB-210814-12
- Date
- 2021
- Source
- PLoS One 16: e0256181 (Journal)
- Registered Authors
- Bhatia, Shipra, van Heyningen, Veronica
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Brain/metabolism
- Brain/pathology
- Chromosome Mapping
- Cohort Studies
- Disease Models, Animal
- Embryo, Nonmammalian
- Exome
- Fragile X Mental Retardation Protein/genetics*
- Fragile X Mental Retardation Protein/metabolism
- Gene Frequency
- Genes, X-Linked*
- Genome, Human*
- Genotype
- Humans
- Male
- Mental Retardation, X-Linked/genetics*
- Mental Retardation, X-Linked/metabolism
- Mental Retardation, X-Linked/pathology
- Mice
- Nerve Tissue Proteins/deficiency
- Nerve Tissue Proteins/genetics*
- Pedigree
- Phenotype
- Regulatory Elements, Transcriptional*
- Tenascin/deficiency
- Tenascin/genetics*
- Zebrafish
- PubMed
- 34388204 Full text @ PLoS One
Citation
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. 16:e0256181.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping