{"doi":"10.1136/jmg.40.6.399","title":"Complete sequencing shows a role for <i>MSX1</i> in non-syndromic cleft lip and palate","abstract":"<jats:p>\n                  <jats:italic>MSX1</jats:italic> has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes clefting as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of <jats:italic>MSX1</jats:italic> (two exons, one intron). We compare the completed genomic sequence of <jats:italic>MSX1</jats:italic> to the mouse <jats:italic>Msx1</jats:italic> sequence to identify non-coding homology regions, and sequence highly conserved elements. The samples studied were drawn from a panethnic collection including people of European, Asian, and native South American ancestry. The gene was sequenced in 917 people and potentially aetiological mutations were identified in 16. These included missense mutations in conserved amino acids and point mutations in conserved regions not identified in any of 500 controls sequenced. Five different missense mutations in seven unrelated subjects with clefting are described. Evolutionary sequence comparisons of all known <jats:italic>Msx1</jats:italic> orthologues placed the amino acid substitutions in context. Four rare mutations were found in non-coding regions that are highly conserved and disrupt probable regulatory regions. In addition, a panel of 18 population specific polymorphic variants were identified that will be useful in future haplotype analyses of <jats:italic>MSX1. MSX1</jats:italic> mutations are found in 2% of cases of clefting and should be considered for genetic counselling implications, particularly in those families in which autosomal dominant inheritance patterns or dental anomalies appear to be cosegregating with the clefting phenotype.</jats:p>","journal":"Journal of Medical Genetics","year":2003,"id":596977,"datarank":0.8590271621380796,"base_score":5.726847747587197,"endowment":5.726847747587197,"self_citation_contribution":0.8590271621380796,"citation_network_contribution":0.0,"self_endowment_contribution":0.8590271621380796,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":306,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1529104,"name":"A R Vieira","orcid":null,"position":1,"is_corresponding":false},{"id":1529105,"name":"C Nishimura","orcid":null,"position":2,"is_corresponding":false},{"id":1529106,"name":"B Ludwig","orcid":null,"position":3,"is_corresponding":false},{"id":1529107,"name":"M Johnson","orcid":null,"position":4,"is_corresponding":false},{"id":1529108,"name":"S E O’Brien","orcid":null,"position":5,"is_corresponding":false},{"id":1529109,"name":"S Daack-Hirsch","orcid":null,"position":6,"is_corresponding":false},{"id":1529110,"name":"R E Schultz","orcid":null,"position":7,"is_corresponding":false},{"id":521642,"name":"A Weber","orcid":null,"position":8,"is_corresponding":false},{"id":1529111,"name":"B Nepomucena","orcid":null,"position":9,"is_corresponding":false},{"id":1529113,"name":"P A Romitti","orcid":null,"position":10,"is_corresponding":false},{"id":1529115,"name":"K Christensen","orcid":null,"position":11,"is_corresponding":false},{"id":1529117,"name":"I M Orioli","orcid":null,"position":12,"is_corresponding":false},{"id":1529119,"name":"E E Castilla","orcid":null,"position":13,"is_corresponding":false},{"id":1529121,"name":"J Machida","orcid":null,"position":14,"is_corresponding":false},{"id":1529122,"name":"N Natsume","orcid":null,"position":15,"is_corresponding":false},{"id":1529123,"name":"J C Murray","orcid":null,"position":16,"is_corresponding":false},{"id":1529103,"name":"P A Jezewski","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Complete sequencing shows a role for <i>MSX1</i> in non-syndromic cleft lip and palate","abstract":"<jats:p>\n                  <jats:italic>MSX1</jats:italic> has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes clefting as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of <jats:italic>MSX1</jats:italic> (two exons, one intron). We compare the completed genomic sequence of <jats:italic>MSX1</jats:italic> to the mouse <jats:italic>Msx1</jats:italic> sequence to identify non-coding homology regions, and sequence highly conserved elements. The samples studied were drawn from a panethnic collection including people of European, Asian, and native South American ancestry. The gene was sequenced in 917 people and potentially aetiological mutations were identified in 16. These included missense mutations in conserved amino acids and point mutations in conserved regions not identified in any of 500 controls sequenced. Five different missense mutations in seven unrelated subjects with clefting are described. Evolutionary sequence comparisons of all known <jats:italic>Msx1</jats:italic> orthologues placed the amino acid substitutions in context. Four rare mutations were found in non-coding regions that are highly conserved and disrupt probable regulatory regions. In addition, a panel of 18 population specific polymorphic variants were identified that will be useful in future haplotype analyses of <jats:italic>MSX1. MSX1</jats:italic> mutations are found in 2% of cases of clefting and should be considered for genetic counselling implications, particularly in those families in which autosomal dominant inheritance patterns or dental anomalies appear to be cosegregating with the clefting phenotype.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"12807959","pmcid":"PMC1735501","openalex_id":null,"authors":[],"funders":[{"funder_name":"NIEHS NIH HHS","grant_id":"ES10876","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"DK25295","title":null},{"funder_name":"NIDCR NIH HHS","grant_id":"P60 DE13076-02","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM007337","title":null},{"funder_name":"ODCDC CDC HHS","grant_id":"U50/CCU 713238","title":null},{"funder_name":"NIDCR NIH HHS","grant_id":"DE11948","title":null},{"funder_name":"FIC NIH HHS","grant_id":"D43 TW05503","title":null},{"funder_name":"NIDCR NIH HHS","grant_id":"DEO8559","title":null},{"funder_name":"National Institutes of Health","grant_id":"5D43TW005503-03","title":"International Maternal &Child Health Research/Training"},{"funder_name":"National Institutes of Health","grant_id":"5P60DE013076-02","title":"HYDROXYAPATITE CEMENT TO SUPPORT DENTAL IMPLANTS"}],"total_grants":10,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"bronze","license":null,"oa_locations":[{"url":"https://syndication.highwire.org/content/doi/10.1136/jmg.40.6.399","host_type":"publisher"},{"url":"https://doi.org/10.1136/jmg.40.6.399","host_type":""},{"url":"https://jmg.bmj.com/content/40/6/399.full.pdf","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/12807959","host_type":""},{"url":"https://dx.doi.org/10.1136/jmg.40.6.399","host_type":""},{"url":"https://portal.findresearcher.sdu.dk/da/publications/894ac1a0-ba9a-11dc-9626-000ea68e967b","host_type":""}],"fields_of_study":["0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Animals","Chickens","Cattle","Humans","Mice","Rats","Cleft Palate","Cleft Lip","Syndrome","Xenopus Proteins","Homeodomain Proteins","Transcription Factors","DNA","Untranslated Regions","Case-Control Studies","Sequence Alignment","DNA Mutational Analysis","Genetics, Population","Amino Acid Sequence","Linkage Disequilibrium","Mutation","Polymorphism, Genetic","Molecular Sequence Data","South America","Asia","Europe","MSX1 Transcription Factor","Genetic Variation"],"keywords":["Homeodomain Proteins","MSX1 Transcription Factor","Asia","Cleft Lip","DNA Mutational Analysis","Molecular Sequence Data","Genetic Variation","DNA","Linkage Disequilibrium","Cleft Palate","Europe","Mice","Genetics, Population","Case-Control Studies","Mutation","Animals","Humans","Cattle","Amino Acid Sequence","Chickens"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-28T11:53:17.825385Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}