Molecular heterogeneity and diagnostic performance of phenotype-driven multigene panel testing in patients with...

Marfanoid habitus represents a clinically heterogeneous phenotype observed in Marfan syndrome (MFS) and other hereditary connective tissue disorders; however, the diagnostic utility of multigene panel testing in this group remains incompletely defined. Marfanoid features encountered in clinical genetics practice are often partial, age-dependent, or overlapping and may not meet diagnostic criteria for a single disorder, limiting phenotype-based classification and supporting multigene testing. We retrospectively evaluated the diagnostic yield of a custom-designed NGS panel targeting OMIM-listed syndromes associated with marfanoid habitus in 62 patients referred between 2016 and 2022. Clinical and molecular data were reviewed, and MFS systemic scores were compared between groups. Variants were identified in 28 of 51 patients analyzed by the panel, including four with FBN1 variants. Based on ACMG criteria and clinical evaluation, 16 cases were classified as clinically definitive, two as clinically high-probability, and ten as clinically suspicious diagnoses. The diagnostic yield was 54.9% overall and 31.3% for clinically definitive cases. Exome sequencing in panel-negative patients identified seven variants across six additional genes. No significant difference in systemic scores was observed between variant-positive and variant-negative cases; however, patients with FBN1 variants had significantly higher scores than those with variants in other genes. ROC analysis demonstrated good discriminatory performance for FBN1-related cases (AUC = 0.80; 95% CI, 0.63-0.94), and each one-point increase in systemic score was associated with a 1.51-fold increase in the odds of harboring an FBN1 variant. These findings support tailored multigene panel testing as an effective diagnostic strategy in patients with marfanoid habitus.