Shin Ju Hyeon, Kim Young-Gon, Jang Shin Yi, Huh June, Kim Duk-Kyung, Kim Jong-Won, Jang Ja-Hyun, Park Taek Kyu, Jang Mi-Ae
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Eur J Hum Genet. 2025 May;33(5):666-674. doi: 10.1038/s41431-025-01826-9. Epub 2025 Apr 1.
Marfan syndrome (MFS) is a genetic disorder caused by an FBN1 variant and is diagnosed based on the revised Ghent criteria, which incorporate clinical manifestations and genetic testing. Up-to-date FBN1 variant interpretation is crucial for proper diagnosis and management of MFS; however, some FBN1 variants of uncertain significance (VUSs) remain inconclusive despite applying Clinical Genome Resource (ClinGen) FBN1-specific guideline. Recently, the ClinGen guidance for PP1/BS4 co-segregation and PP4 phenotype specificity criteria (new PP1/PP4 criteria) were released. Here, we performed reassessment of FBN1 VUSs using these new PP1/PP4 criteria. FBN1 VUSs collected from December 2015 to April 2024 were reassessed according to the ClinGen FBN1-specific guideline and new PP1/PP4 criteria. Medical records and previous studies were reviewed to evaluate the phenotype-specificity of evidence based on the revised Ghent criteria. Collectively, 927 patients with suspected MFS underwent FBN1 sequencing and 72 VUSs were detected. When applying the FBN1-specific guideline only, of 72 VUSs, 29 (40.3%) were reclassified as pathogenic variants (PVs) or likely PVs (LPVs). When additionally applying the new PP1/PP4 criteria, 16 (37.2%) of the remaining 43 VUSs were reclassified as LPVs. After reassessing FBN1 VUSs according to the new PP1/PP4 criteria, the rate of reclassification from VUS to PV/LPV significantly increased from 40.3% to 62.5%. The new PP1/PP4 criteria provide sufficient evidence for evaluating the pathogenicity of FBN1 variants detected in MFS patients fulfilling the revised Ghent criteria and will be helpful in clinical analysis.
马凡综合征（MFS）是一种由FBN1基因变异引起的遗传性疾病，根据修订后的根特标准进行诊断，该标准纳入了临床表现和基因检测。最新的FBN1基因变异解读对于MFS的正确诊断和管理至关重要；然而，尽管应用了临床基因组资源（ClinGen）的FBN1特异性指南，一些意义未明的FBN1基因变异（VUSs）仍然无法得出结论。最近，ClinGen发布了关于PP1/BS4共分离和PP4表型特异性标准的指南（新的PP1/PP4标准）。在此，我们使用这些新的PP1/PP4标准对FBN1 VUSs进行了重新评估。根据ClinGen的FBN1特异性指南和新的PP1/PP4标准，对2015年12月至2024年4月期间收集的FBN1 VUSs进行了重新评估。回顾了病历和先前的研究，以根据修订后的根特标准评估证据的表型特异性。总体而言，927例疑似MFS患者接受了FBN1测序，检测到72个VUSs。仅应用FBN1特异性指南时，在72个VUSs中，29个（40.3%）被重新分类为致病变异（PVs）或可能的致病变异（LPVs）。当另外应用新的PP1/PP4标准时，其余43个VUSs中的16个（37.2%）被重新分类为LPVs。根据新的PP1/PP4标准对FBN1 VUSs进行重新评估后，从VUS重新分类为PV/LPV的比例从40.3%显著增加到62.5%。新的PP1/PP4标准为评估符合修订后根特标准的MFS患者中检测到的FBN1基因变异的致病性提供了充分的证据，将有助于临床分析。
