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<p>Marfan syndrome (MFS) is a genetic disorder caused by an <i>FBN1</i> variant and is diagnosed based on the revised Ghent criteria, which incorporate clinical manifestations and genetic testing. Up-to-date <i>FBN1</i> variant interpretation is crucial for proper diagnosis and management of MFS; however, some <i>FBN1</i> variants of uncertain significance (VUSs) remain inconclusive despite applying Clinical Genome Resource (ClinGen) <i>FBN1</i>-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 <i>FBN1</i> VUSs using these new PP1/PP4 criteria. <i>FBN1</i> VUSs collected from December 2015 to April 2024 were reassessed according to the ClinGen <i>FBN1</i>-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 <i>FBN1</i> sequencing and 72 VUSs were detected. When applying the <i>FBN1</i>-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 <i>FBN1</i> 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 <i>FBN1</i> variants detected in MFS patients fulfilling the revised Ghent criteria and will be helpful in clinical analysis.</p>

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Reassessment of FBN1 variants of uncertain significance using updated ClinGen guidance for PP1/BS4 and PP4 criteria

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月1日

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  • Ju Hyeon Shin,
  • Young-gon Kim,
  • Shin Yi Jang,
  • June Huh,
  • Duk-Kyung Kim,
  • Jong-Won Kim,
  • Ja-Hyun Jang,
  • Taek Kyu Park,
  • Mi-Ae Jang

摘要

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.