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

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 ma...

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Autores principales:	Hemant Bengani, Detelina Grozeva, Lambert Moyon, Shipra Bhatia, Susana R Louros, Jilly Hope, Adam Jackson, James G Prendergast, Liusaidh J Owen, Magali Naville, Jacqueline Rainger, Graeme Grimes, Mihail Halachev, Laura C Murphy, Olivera Spasic-Boskovic, Veronica van Heyningen, Peter Kind, Catherine M Abbott, Emily Osterweil, F Lucy Raymond, Hugues Roest Crollius, David R FitzPatrick
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4eb3db40878647e9883fefc1a958a6db
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spelling	oai:doaj.org-article:4eb3db40878647e9883fefc1a958a6db2021-12-02T20:18:08ZIdentification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.1932-620310.1371/journal.pone.0256181https://doaj.org/article/4eb3db40878647e9883fefc1a958a6db2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0256181https://doaj.org/toc/1932-6203Identifying 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.Hemant BenganiDetelina GrozevaLambert MoyonShipra BhatiaSusana R LourosJilly HopeAdam JacksonJames G PrendergastLiusaidh J OwenMagali NavilleJacqueline RaingerGraeme GrimesMihail HalachevLaura C MurphyOlivera Spasic-BoskovicVeronica van HeyningenPeter KindCatherine M AbbottEmily OsterweilF Lucy RaymondHugues Roest CrolliusDavid R FitzPatrickPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0256181 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hemant Bengani Detelina Grozeva Lambert Moyon Shipra Bhatia Susana R Louros Jilly Hope Adam Jackson James G Prendergast Liusaidh J Owen Magali Naville Jacqueline Rainger Graeme Grimes Mihail Halachev Laura C Murphy Olivera Spasic-Boskovic Veronica van Heyningen Peter Kind Catherine M Abbott Emily Osterweil F Lucy Raymond Hugues Roest Crollius David R FitzPatrick Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.
description	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.
format	article
author	Hemant Bengani Detelina Grozeva Lambert Moyon Shipra Bhatia Susana R Louros Jilly Hope Adam Jackson James G Prendergast Liusaidh J Owen Magali Naville Jacqueline Rainger Graeme Grimes Mihail Halachev Laura C Murphy Olivera Spasic-Boskovic Veronica van Heyningen Peter Kind Catherine M Abbott Emily Osterweil F Lucy Raymond Hugues Roest Crollius David R FitzPatrick
author_facet	Hemant Bengani Detelina Grozeva Lambert Moyon Shipra Bhatia Susana R Louros Jilly Hope Adam Jackson James G Prendergast Liusaidh J Owen Magali Naville Jacqueline Rainger Graeme Grimes Mihail Halachev Laura C Murphy Olivera Spasic-Boskovic Veronica van Heyningen Peter Kind Catherine M Abbott Emily Osterweil F Lucy Raymond Hugues Roest Crollius David R FitzPatrick
author_sort	Hemant Bengani
title	Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.
title_short	Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.
title_full	Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.
title_fullStr	Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.
title_full_unstemmed	Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.
title_sort	identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with x-linked intellectual disability.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/4eb3db40878647e9883fefc1a958a6db
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Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.

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