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Affected tissues typically include the ears (external and internal), mandible, and maxilla, but various extracranial anomalies have also been reported. Loss-of-function variants in the\n                    <jats:italic>SF3B2<\/jats:italic>\n                    gene have recently been reported in 8 cases of CFM, representing one of the more common genetic causes identified to date. To better define the full phenotypic spectrum associated with variants in\n                    <jats:italic>SF3B2<\/jats:italic>\n                    , we report novel loss-of-function variants in\n                    <jats:italic>SF3B2<\/jats:italic>\n                    in 5 new families with CFM. Furthermore, to determine the mechanism by which\n                    <jats:italic>SF3B2<\/jats:italic>\n                    loss-of-function perturbs craniofacial development, we established\n                    <jats:italic>sf3b2<\/jats:italic>\n                    -null mutant zebrafish, which exhibited severe deficiencies in craniofacial cartilage and bone progenitors due to elevated apoptosis and reduced proliferation of cranial neural crest cells. In addition, we generated a heterozygous truncating variant of\n                    <jats:italic>SF3B2<\/jats:italic>\n                    in human induced pluripotent stem cells using CRISPR\/Cas9 gene editing. Differentiation of these cells into neural crest cells was accompanied by increased cell death and reduced proliferation. RNA sequencing of\n                    <jats:italic>sf3b2<\/jats:italic>\n                    mutant zebrafish revealed widespread disruption of mRNA splicing, including\n                    <jats:italic>mdm2<\/jats:italic>\n                    , a key regulator of Tp53-mediated apoptosis. Genetic inhibition of\n                    <jats:italic>tp53<\/jats:italic>\n                    in\n                    <jats:italic>sf3b2<\/jats:italic>\n                    mutants demonstrated that\n                    <jats:italic>tp53<\/jats:italic>\n                    inhibition reduces early cell death but does not improve proliferation or craniofacial cartilage development. Therefore, our functional studies indicate that widespread mRNA splicing disruption, in addition to Tp53-dependent cell death, contributes to the craniofacial features observed in\n                    <jats:italic>SF3B2<\/jats:italic>\n                    -related CFM.\n                  <\/jats:p>","DOI":"10.1177\/00220345251325818","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T02:44:22Z","timestamp":1745549062000},"page":"1116-1126","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Splicing Defects and Cell Death Cause\n                    <i>SF3B2<\/i>\n                    -Linked Craniofacial Microsomia"],"prefix":"10.1177","volume":"104","author":[{"given":"S.","family":"Rao","sequence":"first","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, University of Missouri\u2013Kansas City, Kansas City, MO, 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