The usefulness of the genetic panel in the classification and refinement of diagnostic accuracy of Mexican patients with Marfan syndrome and other connective tissue disorders

Figures

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  Figure 1.. Mutations reported by NGS in Marfan-like disorders. Global frequency of reported mutations with clinical value. A total of 64 MFS patients presented mutations in FBN1; three patients had, in addition to the FBN1 gene mutation, mutations in other genes: AKAP9, COL5A1, and GCKR. We found 16 patients with LDS, all with mutations in genes associated with LDS: 11 in TGFBR2, three in TGFBR1, one in TGFB2, and one of them also had a mutation that coexists with FBN1. BHS and EDS patients showed mutations in FBN2 and COL5A1, respectively, overlapping with different mutations. The NCTD group showed mutations in genes associated with cardiomyopathies and arrhythmias. NGS: Next-generation sequencing; MFS: Marfan syndrome; LDS: Loeys–Dietz syndrome; BHS: Beals–Hecht syndrome; EDS: Ehlers–Danlos syndrome; WMS: Weill–Marchesani syndrome; NCTD: Nonspecific connective tissue disease; FBN1: Fibrillin 1; TGFBR2: Transforming growth factor beta receptor 2.

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  Figure 2.. Diagnosis based on clinical characteristics vs clinical and genetic diagnosis: In the clinical evaluation based on four clinical criteria (AHF, aortic dilatation, ectopia lentis, and systemic score), 75 cases were identified as MFS. Reclassification of diagnosis was conducted using a multipanel genetic test. For example, out of the 75 initially considered as MFS due to meeting more than two clinical criteria (without the multipanel genetic test), only 64 were classified as MFS after the test. In the MFS + FBN1 column, it is seen that only 53 (71%) were confirmed as MFS, while 22 (29%) were reclassified after the test (highlighted in blue): six as LDS, eight as BHS, three as EDS, and five as NCTD. In this column, in addition to the 53 confirmed as MFS, 11 other patients were reclassified: nine initially diagnosed as LDS, one as EDS, and one as MASS. Similar reclassifications were observed in the other columns corresponding to other diagnoses. The same in the other columns with the other diagnoses. MFS: Marfan syndrome; LDS: Loeys–Dietz syndrome; BHS: Beals–Hecht syndrome; EDS: Ehlers–Danlos syndrome; WMS: Weill–Marchesani syndrome; NCTD: Nonspecific connective tissue disease;…

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  Figure 3.. Type of mutation and reported severity grouped by syndrome studied. VUS: Variants of unknown significance; NCTD: Nonspecific connective tissue disease; Path: Pathogenic.

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  Figure 4.. Distance matrix represented in a heat map. (A) Mutation severity and the four Ghent criteria; (B) Type of mutation and the four Ghent criteria. Clinical criteria are presented as presences (light blue) and absences (dark blue). Clinical criteria are depicted with color differentiation—presence in light blue and absence in dark blue. Each row represents an individual patient, allowing for a patient–centric view of the data. As you move horizontally from left to right, the color intensity (ranging from intense to low blue) signifies the presence or absence of a Ghent clinical criterion. Further to the right, a column with a distinct color represents the severity of the variant, followed by another column indicating the type of syndrome. For statistical interpretation, two specific columns are of focus—one identifying the type of syndrome and the other visually representing the severity of the variant. By examining these columns, one can discern, from right to left, the proportion of patients with MFS exhibiting a particular variant type, which, in turn, correlates with the presence of certain clinical criteria. MFS: Marfan syndrome; LDS: Loeys–Dietz syndrome; BHS: Beals–Hecht…