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The association between SF3B2 and craniofacial microsomia is supported by multiple lines of evidence from case reports, multi‐patient studies, and functional assays. Craniofacial microsomia (CFM) is a common congenital malformation affecting facial structure, and SF3B2 loss‐of‐function variants have been implicated in the pathogenesis of the disorder (PMID:37555391). In affected individuals, heterozygous variants lead to a haploinsufficient state that disrupts normal spliceosomal function, providing a mechanistic link to the observed craniofacial anomalies. Early reports from singular case analyses have been bolstered by subsequent studies that identified multiple affected probands across independent kindreds. These cumulative data underscore the clinical relevance of SF3B2 in CFM. The integration of genetic discoveries with experimental validation renders the association both biologically and clinically compelling.
Comprehensive genetic evaluation has revealed that SF3B2‐related CFM follows an autosomal dominant pattern of inheritance. Segregation analysis in familial cases revealed that additional affected relatives, including direct transmissions from an affected parent, support the pathogenic role of SF3B2 variants (PMID:37555391). Detailed case series have reported loss‐of‐function and splicing variants that disrupt the gene’s normal function. For instance, a recurrent variant, c.1912C>T (p.Arg638Ter), has been observed in multiple independent families, consistent with a haploinsufficiency model. In total, more than twenty individuals across several kindreds have been documented with pathogenic variants, with in‐depth segregation analysis further strengthening the genotype–phenotype correlation (PMID:34344887). This robust genetic evidence justifies a strong gene–disease association.
At the variant level, the detection of truncating mutations and splice‐site alterations in SF3B2 corroborates the haploinsufficiency mechanism underlying CFM. The variant c.1912C>T (p.Arg638Ter) serves as a representative example of the loss‐of‐function events observed in affected individuals. Molecular investigations, including minigene assays and RNA splicing analyses, have confirmed that such variants lead to premature termination of the protein product. The absence of these variants in population databases like gnomAD further supports their pathogenicity. Additionally, familial segregation—with affected relatives carrying the same variant—reinforces their clinical significance. This variant spectrum, enriched for loss‐of‐function changes, is a critical component of the genetic evidence for SF3B2‐linked CFM.
Functional studies provide compelling experimental support for the role of SF3B2 in craniofacial development. Animal models, notably sf3b2‐null zebrafish, demonstrate marked deficiencies in craniofacial cartilage formation and neural crest cell development. Parallel in vitro experiments using human induced pluripotent stem cells with engineered truncating variants recapitulate abnormal splicing and increased cell death. These data collectively indicate that disrupted splicing, via haploinsufficiency of SF3B2, is a driving factor in the pathogenesis of CFM (PMID:40275713). The experimental concordance between in vivo models and cellular systems underscores the biological impact of SF3B2 dosage on craniofacial morphogenesis.
There is no substantive conflicting genetic or experimental evidence challenging the association of SF3B2 with craniofacial microsomia. Although SF3B2 has been implicated in other conditions such as prostate cancer, the distinct phenotypic spectrum and mechanistic underpinnings in CFM have been consistently validated. The convergence of genetic data, segregation patterns, and functional assays precludes any significant alternative interpretations for the observed craniofacial anomalies. This clarity in the evidence base enhances the reliability of SF3B2 as a diagnostic marker for CFM.
In conclusion, the integration of multi‐family segregation data, a recurrent loss‐of‐function variant spectrum, and concordant functional evidence establishes a strong association between SF3B2 and craniofacial microsomia. This compelling body of evidence supports the use of SF3B2 variant screening in the diagnostic evaluation and genetic counseling of individuals with CFM. Key take‑home: SF3B2 is a clinically actionable gene in craniofacial microsomia, enabling informed diagnostic decision‑making and targeted clinical management.
Gene–Disease AssociationStrongOver 20 individuals from multiple kindreds with confirmed segregation and robust loss‐of‐function evidence support the association (PMID:34344887; PMID:37555391). Genetic EvidenceStrongMultiple truncating and splicing variants, including c.1912C>T (p.Arg638Ter), have been identified across independent families, establishing a recurrent loss‐of‐function profile (PMID:34344887). Functional EvidenceModerateFunctional assays in zebrafish and human iPSC models demonstrate that SF3B2 haploinsufficiency disrupts splicing and craniofacial development, providing supportive experimental data (PMID:40275713). |