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The extent to which genetic risk factors are shared between CL\/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) causes not only spinal NTDs in Axial defects (Axd) mice but also multiple additional defects affecting the cranial region. These include orofacial clefts comprising midline cleft lip and palate and abnormalities of the craniofacial bones and frontal and\/or basal encephalocele, in which brain tissue herniates through the cranium or into the nasal cavity. To investigate the causative mutation in the Grhl2Axd strain, whole genome sequencing identified an approximately 4\u00a0kb LTR retrotransposon insertion that disrupts the non-coding regulatory region, lying approximately 300 base pairs upstream of the 5\u2019 UTR. This insertion also lies within a predicted long non-coding RNA, oriented on the reverse strand, which like Grhl2 is over-expressed in Axd (Grhl2Axd) homozygous mutant embryos. Initial analysis of the GRHL2 upstream region in individuals with NTDs or cleft palate revealed rare or novel variants in a small number of cases. We hypothesize that mutations affecting the regulation of GRHL2 may contribute to craniofacial anomalies and NTDs in humans.<\/jats:p>","DOI":"10.1093\/hmg\/ddad094","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T18:47:52Z","timestamp":1687805272000},"page":"2681-2692","source":"Crossref","is-referenced-by-count":12,"title":["A non-coding insertional mutation of<i>Grhl2<\/i>causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele"],"prefix":"10.1093","volume":"32","author":[{"given":"Zoe","family":"Crane-Smith","sequence":"first","affiliation":[{"name":"University College London Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra C P","family":"De Castro","sequence":"additional","affiliation":[{"name":"University College London Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evanthia","family":"Nikolopoulou","sequence":"additional","affiliation":[{"name":"University College London Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Wolujewicz","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine Center for Neurogenetics, Brain and Mind Research Institute, , New York, New York 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Smedley","sequence":"additional","affiliation":[{"name":"Queen Mary University of London William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, , London EC1M 6BQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunping","family":"Lei","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Center for Precision Environmental Health, Department of Molecular and Cellular Biology, , Houston, Texas 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Mather","sequence":"additional","affiliation":[{"name":"University College London Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe","family":"Santos","sequence":"additional","affiliation":[{"name":"University College London Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hopkinson","sequence":"additional","affiliation":[{"name":"Royal Veterinary College Department of Comparative Biomedical Sciences, , London NW1 0TU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A","family":"Pitsillides","sequence":"additional","affiliation":[{"name":"Royal Veterinary College Department of Comparative Biomedical Sciences, , London NW1 0TU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Genomics England Research Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard H","family":"Finnell","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Center for Precision Environmental Health, Department of Molecular and Cellular Biology, , Houston, Texas 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Elisabeth","family":"Ross","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine Center for Neurogenetics, Brain and Mind Research Institute, , New York, New York 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J","family":"Copp","sequence":"additional","affiliation":[{"name":"University College London Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4170-5248","authenticated-orcid":false,"given":"Nicholas D E","family":"Greene","sequence":"additional","affiliation":[{"name":"University College London Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,6,26]]},"reference":[{"key":"2023082708541188500_ref1","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/ajmg.c.31381","article-title":"Genetics of cleft lip and cleft palate","volume":"163C","author":"Leslie","year":"2013","journal-title":"Am. 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