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We have used <jats:italic>in vivo<\/jats:italic> 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, <jats:italic>FMR1<\/jats:italic><jats:sup>CRE<\/jats:sup> and <jats:italic>TENM1<\/jats:italic><jats:sup>CRE<\/jats:sup>, 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 <jats:italic>Fmr1<\/jats:italic><jats:sup>CRE<\/jats:sup> induced alterations in neurodevelopmental <jats:italic>Fmr1<\/jats:italic> expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported <jats:italic>FMR1<\/jats:italic><jats:sup>CRE<\/jats:sup> as the likely basis of the XLID in this family. <jats:italic>Tenm1<\/jats:italic><jats:sup>CRE<\/jats:sup> mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that <jats:italic>TENM1<\/jats:italic><jats:sup>CRE<\/jats:sup> 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0256181","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T17:40:56Z","timestamp":1628876456000},"page":"e0256181","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability"],"prefix":"10.1371","volume":"16","author":[{"given":"Hemant","family":"Bengani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3239-8415","authenticated-orcid":true,"given":"Detelina","family":"Grozeva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-3942","authenticated-orcid":true,"given":"Lambert","family":"Moyon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2091-7858","authenticated-orcid":true,"given":"Shipra","family":"Bhatia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1012-0386","authenticated-orcid":true,"given":"Susana R.","family":"Louros","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jilly","family":"Hope","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3554-6682","authenticated-orcid":true,"given":"Adam","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8916-018X","authenticated-orcid":true,"given":"James G.","family":"Prendergast","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0363-1775","authenticated-orcid":true,"given":"Liusaidh J.","family":"Owen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6821-2427","authenticated-orcid":true,"given":"Magali","family":"Naville","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Rainger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3106-5996","authenticated-orcid":true,"given":"Graeme","family":"Grimes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4594-4588","authenticated-orcid":true,"given":"Mihail","family":"Halachev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0029-0434","authenticated-orcid":true,"given":"Laura C.","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1583-8132","authenticated-orcid":true,"given":"Olivera","family":"Spasic-Boskovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0359-0141","authenticated-orcid":true,"given":"Veronica","family":"van Heyningen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Kind","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8794-7173","authenticated-orcid":true,"given":"Catherine M.","family":"Abbott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0582-2284","authenticated-orcid":true,"given":"Emily","family":"Osterweil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F. 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