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In recent years, coat proteins have been implicated in human diseases known collectively as \u201ccoatopathies\u201d.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in <jats:italic>COPB1<\/jats:italic>, which encodes the beta-subunit of COPI (\u03b2-COP). To investigate Family 1\u2019s splice donor site variant, we undertook patient blood RNA studies and CRISPR\/Cas9 modelling of this variant in a homologous region of the <jats:italic>Xenopus tropicalis<\/jats:italic> genome. To investigate Family 2\u2019s missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a <jats:italic>COPB1<\/jats:italic> expression vector into which we had introduced Family 2\u2019s mutation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in <jats:italic>COPB1<\/jats:italic> pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between \u03b2-COP and \u03b2\u2019-COP. <jats:italic>Xenopus tropicalis<\/jats:italic> animals with a homologous mutation, introduced by CRISPR\/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the <jats:italic>COPB1<\/jats:italic> c.1651T&gt;G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant \u03b2-COP, with the mutant protein being retarded in the Golgi.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with <jats:italic>Xenopus tropicalis<\/jats:italic> CRISPR\/Cas modelling for the identification and characterisation of novel rare disease genes.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13073-021-00850-w","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T15:07:24Z","timestamp":1614265644000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0612-5819","authenticated-orcid":false,"given":"William L.","family":"Macken","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Godwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Wheway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Stals","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliya","family":"Nazlamova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian","family":"Ellard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Alfares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taghrid","family":"Aloraini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamia","family":"AlSubaie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Alfadhel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulaiman","family":"Alajaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Htoo A.","family":"Wai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Self","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G. 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This study was approved by South Central \u2013 Oxford B Research Ethics Committee (REC Reference 11\/SC\/0269, IRAS ID 49685). Family 2 were enrolled in a large genome sequencing study for undiagnosed disease. Ethical approval for Family 2\u2019s study was granted by the Institutional Research Board of King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (RC 16\/113 and RC16\/211\/R2). Written informed consent to participate was obtained from the legal guardians for all subjects involved in this study as none had the capacity to consent for themselves. All research conformed with the principles of the Declaration of Helsinki. <i>Xenopus<\/i> experiments were conducted in accordance with the Home Office Code of Practice, under PPL 70\/8983 with approval from the University of Portsmouth\u2019s Animal Welfare and Ethical Review Body.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication of identifiable data was obtained for Family 1 and 2 from the legal guardians of the participants. Consent included the publication of genetic sequence information and clinical information for both families and for clinical photographs for Family 1 only.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"34"}}