ClinGen Bayesian-Framework-Guided Interpretation of Compound Heterozygous F12 Variants in a Pregnant Woman with...

Background and Clinical Significance: Isolated prolongation of activated partial thromboplastin time (aPTT) without a bleeding tendency presents a frequent diagnostic challenge and often leads to prolonged, inconclusive evaluations. Case Presentation: We report the case of a pregnant woman with long-standing isolated aPTT prolongation in whom clinical exome sequencing enabled a definitive diagnosis. Two compound heterozygous variants in F12 were identified: NM_000505.4:c.1561G>A, p.(Glu521Lys), previously reported in Factor XII deficiency, and a novel in-frame insertion, NM_000505.4:c.1423_1425dup, p.(Cys475dup), absent from population databases and the prior literature. Familial genetic testing confirmed a trans configuration. Factor XII activity was markedly reduced to 1%, and mixing studies showed complete correction, consistent with coagulation factor deficiency without inhibitors. Variant interpretation using ClinGen specifications within a Bayesian framework classified both variants as likely pathogenic. Despite significant laboratory abnormalities, the patient experienced no bleeding or thrombotic complications and underwent cesarean delivery without adverse events. Conclusions: This case highlights that early integration of next-generation sequencing and quantitative variant interpretation frameworks can facilitate timely diagnosis, clarify clinical significance, and support appropriate management in patients with unexplained isolated aPTT prolongation.