Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.

Autor:	Bengani H; MRC Human Genetics Unit, IGMM, University of Edinburgh (UoE), Edinburgh, United Kingdom., Grozeva D; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.; Institute of Psychological Medicine & Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom., Moyon L; Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris, France., Bhatia S; MRC Human Genetics Unit, IGMM, University of Edinburgh (UoE), Edinburgh, United Kingdom., Louros SR; Centre for Discovery Brain Sciences, Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom., Hope J; Institute of Genomic and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Jackson A; Centre for Discovery Brain Sciences, Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom., Prendergast JG; Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom., Owen LJ; MRC Human Genetics Unit, IGMM, University of Edinburgh (UoE), Edinburgh, United Kingdom., Naville M; Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris, France., Rainger J; MRC Human Genetics Unit, IGMM, University of Edinburgh (UoE), Edinburgh, United Kingdom., Grimes G; Institute of Genomic and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Halachev M; Institute of Genomic and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Murphy LC; Institute of Genomic and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Spasic-Boskovic O; East Midlands and East of England NHS Genomic Laboratory Hub, Molecular Genetics, Adden brooke's Hospital, Cambridge University Hospitals NHS Foundation Trust Cambridge, Cambridge, United Kingdom., van Heyningen V; MRC Human Genetics Unit, IGMM, University of Edinburgh (UoE), Edinburgh, United Kingdom., Kind P; Centre for Discovery Brain Sciences, Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom., Abbott CM; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom.; Institute of Genomic and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Osterweil E; Centre for Discovery Brain Sciences, Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom., Raymond FL; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom., Roest Crollius H; Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris, France., FitzPatrick DR; MRC Human Genetics Unit, IGMM, University of Edinburgh (UoE), Edinburgh, United Kingdom.; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2021 Aug 13; Vol. 16 (8), pp. e0256181. Date of Electronic Publication: 2021 Aug 13 (Print Publication: 2021).
DOI:	10.1371/journal.pone.0256181
Abstrakt:	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. Competing Interests: No authors have competing interests
Databáze:	MEDLINE
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