{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T15:59:31Z","timestamp":1765382371713,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DEFI\u2014Departamento de Ensino, Forma\u00e7\u00e3o e Investiga\u00e7\u00e3o, Centro Hospitalar Universit\u00e1rio do Porto","award":["BI.03\/2018\/HEMATCLINICA\/CHP","UIDB\/00215\/2020","UIDP\/00215\/2020","LA\/P\/0064\/2020"],"award-info":[{"award-number":["BI.03\/2018\/HEMATCLINICA\/CHP","UIDB\/00215\/2020","UIDP\/00215\/2020","LA\/P\/0064\/2020"]}]},{"name":"F\u00f3rum Hematol\u00f3gico do Norte","award":["BI.03\/2018\/HEMATCLINICA\/CHP","UIDB\/00215\/2020","UIDP\/00215\/2020","LA\/P\/0064\/2020"],"award-info":[{"award-number":["BI.03\/2018\/HEMATCLINICA\/CHP","UIDB\/00215\/2020","UIDP\/00215\/2020","LA\/P\/0064\/2020"]}]},{"name":"Foundation for Science and Technology (FCT) Portugal","award":["BI.03\/2018\/HEMATCLINICA\/CHP","UIDB\/00215\/2020","UIDP\/00215\/2020","LA\/P\/0064\/2020"],"award-info":[{"award-number":["BI.03\/2018\/HEMATCLINICA\/CHP","UIDB\/00215\/2020","UIDP\/00215\/2020","LA\/P\/0064\/2020"]}]},{"name":"ITR\u2014Laboratory for Integrative and Translational Research in Population Health","award":["BI.03\/2018\/HEMATCLINICA\/CHP","UIDB\/00215\/2020","UIDP\/00215\/2020","LA\/P\/0064\/2020"],"award-info":[{"award-number":["BI.03\/2018\/HEMATCLINICA\/CHP","UIDB\/00215\/2020","UIDP\/00215\/2020","LA\/P\/0064\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by the bilateral absence of the radius and thrombocytopenia, and sometimes by other skeletal, gastrointestinal, cardiac, and renal abnormalities. The underlying genetic defect is usually the compound inheritance of a microdeletion in 1q21.1 (null allele) and a low-frequency, non-coding single nucleotide variant (SNV) in the RBM8A gene (hypomorphic allele). We report three new cases from two unrelated families. The two siblings presented the common genotype, namely the compound heterozygosity for a 1q21.1 microdeletion and the hypomorphic SNV c.-21G&gt;A in RBM8A, whereas the third, unrelated patient presented a rare genotype comprised by two RBM8A variants: c.-21G&gt;A (hypomorphic allele) and a novel pathogenic variant, c.343-2A&gt;G (null allele). Of the eight documented RBM8A variants identified in TAR syndrome patients, four have hypomorphic expression and four behave as null alleles. The present report expands the RBM8A null allele spectrum and corroborates the particularities of RBM8A involvement in TAR syndrome pathogenesis.<\/jats:p>","DOI":"10.3390\/ijms23179621","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T21:28:12Z","timestamp":1661462892000},"page":"9621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Thrombocytopenia-Absent Radius Syndrome: Descriptions of Three New Cases and a Novel Splicing Variant in RBM8A That Expands the Spectrum of Null Alleles"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6659-4951","authenticated-orcid":false,"given":"Catarina","family":"Monteiro","sequence":"first","affiliation":[{"name":"Unidade de Gen\u00e9tica Molecular, Centro de Gen\u00e9tica M\u00e9dica Doutor Jacinto Magalh\u00e3es, Centro Hospitalar Universit\u00e1rio do Porto, 4099-028 Porto, Portugal"},{"name":"Servi\u00e7o de Hematologia Cl\u00ednica, Unidade de Trombose e Hemostase, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica (UMIB), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS) e Laborat\u00f3rio Para a Investiga\u00e7\u00e3o Integrativa e Translacional em Sa\u00fade Populacional (ITR), Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3917-2323","authenticated-orcid":false,"given":"Ana","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Unidade de Gen\u00e9tica Molecular, Centro de Gen\u00e9tica M\u00e9dica Doutor Jacinto Magalh\u00e3es, Centro Hospitalar Universit\u00e1rio do Porto, 4099-028 Porto, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica (UMIB), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS) e Laborat\u00f3rio Para a Investiga\u00e7\u00e3o Integrativa e Translacional em Sa\u00fade Populacional (ITR), Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3924-6385","authenticated-orcid":false,"given":"Jorge","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Unidade de Gen\u00e9tica Molecular, Centro de Gen\u00e9tica M\u00e9dica Doutor Jacinto Magalh\u00e3es, Centro Hospitalar Universit\u00e1rio do Porto, 4099-028 Porto, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica (UMIB), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS) e Laborat\u00f3rio Para a Investiga\u00e7\u00e3o Integrativa e Translacional em Sa\u00fade Populacional (ITR), Universidade do Porto, 4050-313 Porto, Portugal"}]},{"given":"Ramon","family":"Salvado","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Imunohemoterapia, Centro Hospitalar Universit\u00e1rio de Coimbra, 3000-075 Coimbra, Portugal"}]},{"given":"Jorge","family":"Tomaz","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Imunohemoterapia, Centro Hospitalar Universit\u00e1rio de Coimbra, 3000-075 Coimbra, Portugal"}]},{"given":"Sara","family":"Morais","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Hematologia Cl\u00ednica, Unidade de Trombose e Hemostase, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica (UMIB), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS) e Laborat\u00f3rio Para a Investiga\u00e7\u00e3o Integrativa e Translacional em Sa\u00fade Populacional (ITR), Universidade do Porto, 4050-313 Porto, Portugal"}]},{"given":"Margarida","family":"Lima","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Hematologia Cl\u00ednica, Unidade de Trombose e Hemostase, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica (UMIB), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS) e Laborat\u00f3rio Para a Investiga\u00e7\u00e3o Integrativa e Translacional em Sa\u00fade Populacional (ITR), Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8594-6377","authenticated-orcid":false,"given":"Ros\u00e1rio","family":"Santos","sequence":"additional","affiliation":[{"name":"Unidade de Gen\u00e9tica Molecular, Centro de Gen\u00e9tica M\u00e9dica Doutor Jacinto Magalh\u00e3es, Centro Hospitalar Universit\u00e1rio do Porto, 4099-028 Porto, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica (UMIB), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS) e Laborat\u00f3rio Para a Investiga\u00e7\u00e3o Integrativa e Translacional em Sa\u00fade Populacional (ITR), Universidade do Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1136\/jmg.24.2.79","article-title":"Thrombocytopenia and absent radius (TAR) syndrome","volume":"24","author":"Hall","year":"1987","journal-title":"J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1055\/s-0031-1291381","article-title":"Thrombocytopenia-absent radius syndrome","volume":"37","author":"Toriello","year":"2011","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.gde.2013.02.015","article-title":"New insights into the genetic basis of TAR (thrombocytopenia-absent radii) syndrome","volume":"23","author":"Albers","year":"2013","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1086\/510919","article-title":"Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome","volume":"80","author":"Klopocki","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1136\/jmg.39.12.876","article-title":"Thrombocytopenia-absent radius syndrome: A clinical genetic study","volume":"39","author":"Greenhalgh","year":"2002","journal-title":"J. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/ng.1083","article-title":"Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome","volume":"44","author":"Albers","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"a004564","DOI":"10.1101\/mcs.a004564","article-title":"1Q21.1 Deletion and a Rare Functional Polymorphism in Siblings with Thrombocytopenia-Absent Radius-Like Phenotypes","volume":"5","author":"Brodie","year":"2019","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1002\/humu.24021","article-title":"TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A","volume":"41","author":"Boussion","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1399-0004.2012.01888.x","article-title":"Deficiency of the Y14 protein is a critical factor underlying the etiology of thrombocytopenia with absent radii syndrome","volume":"82","author":"Jan","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1006\/geno.1999.6064","article-title":"MAGOH interacts with a novel RNA-binding protein","volume":"63","author":"Zhao","year":"2000","journal-title":"Genomics"},{"key":"ref_11","first-page":"912","article-title":"The pathogenesis of radial ray deficiency in thrombocytopenia-absent radius (TAR) syndrome","volume":"26","year":"2016","journal-title":"J. Coll. Physicians Surg. Pak."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13039-015-0188-6","article-title":"Thrombocytopenia-absent radius (TAR) syndrome due to compound inheritance for a 1q21.1 microdeletion and a low-frequency noncoding RBM8A SNP: A new familial case","volume":"8","author":"Tassano","year":"2015","journal-title":"Mol. Cytogenet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1006\/geno.2000.6315","article-title":"Identification and structural analysis of human RBM8A and RBM8B: Two highly conserved RNA-binding motif proteins that interact with OVCA1, a candidate tumor suppressor","volume":"69","author":"Salicioni","year":"2000","journal-title":"Genomics"},{"key":"ref_14","first-page":"47","article-title":"Trombocitopenia e Aus\u00eancia de R\u00e1dio (S\u00edndrome TAR)\u2014Caso Cl\u00ednico","volume":"32","author":"Silva","year":"2001","journal-title":"Acta Pedi\u00e1trica Port."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.tjog.2020.01.024","article-title":"Upper limb phocomelia: A prenatal case of thrombocytopenia-absent radius (TAR) syndrome illustrating the importance of chromosomal microarray in limb reduction defects","volume":"59","author":"Travessa","year":"2020","journal-title":"Taiwan. J. Obstet. Gynecol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bottillo, I., Castori, M., De Bernardo, C., Fabbri, R., Grammatico, B., Preziosi, N., Scassellati, G.S., Silvestri, E., Spagnuolo, A., and Laino, L. (2013). Prenatal diagnosis and post-mortem examination in a fetus with thrombocytopenia-absent radius (TAR) syndrome due to compound heterozygosity for a 1q21.1 microdeletion and a RBM8A hypomorphic allele: A case report. BMC Res. Notes, 6.","DOI":"10.1186\/1756-0500-6-376"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3892\/mmr.2013.1788","article-title":"Prenatal detection of TAR syndrome in a fetus with compound inheritance of an RBM8A SNP and a 334-kb deletion: A case report","volume":"9","author":"Papoulidis","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/humu.24145","article-title":"A new case of TAR syndrome confirms the importance of noncoding variants in the etiopathogenesis of the disease","volume":"42","author":"Morgan","year":"2021","journal-title":"Hum. Mutat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1111\/bjh.14913","article-title":"Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome","volume":"179","author":"Manukjan","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1111\/ijlh.12516","article-title":"Molecular diagnosis of thrombocytopenia-absent radius syndrome using next-generation sequencing","volume":"38","author":"Nicchia","year":"2016","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_21","first-page":"81","article-title":"Thrombocytopenia absent radius syndrome with tetralogy of fallot: A rare association","volume":"8","author":"Kumar","year":"2015","journal-title":"Int. Med. Case Rep. J."},{"key":"ref_22","first-page":"e23991","article-title":"Thrombocytopenia with Absent Radii Syndrome with an Unusual Urological Pathology: A Case Report","volume":"14","author":"Farlett","year":"2022","journal-title":"Cureus"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1111\/cge.14041","article-title":"Congenital limb deficiency: Genetic investigation of 44 individuals presenting mainly longitudinal defects in isolated or syndromic forms","volume":"100","author":"Pires","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.jbiotec.2020.02.011","article-title":"Expanding the phenotype of thrombocytopenia absent radius syndrome with hypospadias","volume":"311","author":"Maltese","year":"2020","journal-title":"J. Biotechnol."},{"key":"ref_25","first-page":"711","article-title":"Genetic Study and Prenatal Diagnosis of a Family with Thrombocytopenia-Absent Radius (TAR) Syndrome","volume":"52","author":"Key","year":"2021","journal-title":"J. Sichuan Univ. Med. Sci. Ed."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.clinbiochem.2014.04.018","article-title":"A new approach for molecular diagnosis of TAR syndrome","volume":"47","author":"Yassaee","year":"2014","journal-title":"Clin. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9621\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:15:01Z","timestamp":1760141701000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9621"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,25]]},"references-count":26,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms23179621"],"URL":"https:\/\/doi.org\/10.3390\/ijms23179621","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,8,25]]}}}