Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients.

PURPOSE: Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. METHODS: We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. RESULTS: We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. CONCLUSION: Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.

Primary antiphospholipid syndrome in the elderly: Four strokes and mechanical thrombectomies until the diagnosis - A case report.

Antiphospholipid syndrome (APS) is known as a rare etiology of embolic ischemic stroke. In individuals below 50 years, up to 20% of strokes are associated with APS, whereas in patients >50 years, it is considered a very seldom cause of stroke. We describe the course of a 66-year-old white woman, who experienced four embolic strokes with large vessel occlusion over a period of 2 years, which were repeatedly and successfully treated by mechanical thrombectomy. Initially attributed to atrial fibrillation and treated with direct oral anticoagulants, the patient was finally diagnosed with primary APS due to isolated anti-beta 2-glycoprotein antibodies and successfully treated after several stroke recurrences. After initiation of Vitamin K antagonist therapy, no further strokes occurred. For recurrent embolic stroke despite oral anticoagulation, late-onset APS might be considered a rare etiology also in the elderly.