In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 8 ( 2021-8-13), p. 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, FMR1 CRE and TENM1 CRE , 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 Fmr1 CRE 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 FMR1 CRE as the likely basis of the XLID in this family. Tenm1 CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1 CRE 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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0256181
DOI:
10.1371/journal.pone.0256181.g001
DOI:
10.1371/journal.pone.0256181.g002
DOI:
10.1371/journal.pone.0256181.g003
DOI:
10.1371/journal.pone.0256181.g004
DOI:
10.1371/journal.pone.0256181.g005
DOI:
10.1371/journal.pone.0256181.g006
DOI:
10.1371/journal.pone.0256181.g007
DOI:
10.1371/journal.pone.0256181.t001
DOI:
10.1371/journal.pone.0256181.t002
DOI:
10.1371/journal.pone.0256181.s001
DOI:
10.1371/journal.pone.0256181.s002
DOI:
10.1371/journal.pone.0256181.s003
DOI:
10.1371/journal.pone.0256181.s004
DOI:
10.1371/journal.pone.0256181.s005
DOI:
10.1371/journal.pone.0256181.r001
DOI:
10.1371/journal.pone.0256181.r002
DOI:
10.1371/journal.pone.0256181.r003
DOI:
10.1371/journal.pone.0256181.r004
DOI:
10.1371/journal.pone.0256181.r005
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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