Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2

The pathophysiology of thoracic aortic aneurysms and dissections(TAAD) is complex and multifactorial. Classic cardiovascular risk fac-tors play an important role in a majority of patients but genetic fac-tors should always be considered, especially in younger subjectsand/or in the presence of a family history of TAAD. To date, severalgenes have been identified in both syndromic and non-syndromicforms of TAAD, including FBN1 (Marfan syndrome, MFS), TGFBR1/2(Loeys-Dietz syndrome, LDS), SMAD3 (Aneurysm-Osteoarthritissyndrome, AOS), ACTA2 (TAA6, TAAD with livedo reticularis and irisflocculi), MYH11 (TAAD with patent ductus arteriosus), and MYLK(TAAD7) [1–7]. Although clinical features show significant overlap,these entities differ in the extent of vascular involvement and clinicalcourse. As a consequence, molecular studies have become pivotal inthe evaluation, counselling and management of the patient withTAAD. Moreover, the identification of new genes has led to new in-sights into the pathogenesis of aneurysm formation.The crucial role of the transforming-growth-factor β (TGFβ)pathwayin TAAD became evident from both studies on mouse models and theanalysis of components of the TGF β pathway on human aortic tissue ofpatients with these disorders [3,8–11].WepreviouslysequencedTGFB2as a candidate gene for TAAD, but did not identify mutations in 40 pa-tients with isolated aortic root dilatation (Callewaert et al., unpublishedresults). The recent findings by Boileau and colleagues identifying thefirst TGFB2 mutations leading to familial TAAD in association with cere-brovascular disease and mild systemic features reminiscent of Marfansyndrome [16] have urged us toscreenthis geneinapatientgroupasso-ciatingTAADwithawiderphenotypicspectrumincludingcerebrovascu-lar disease, arterial tortuosity, ma rfanoid skeletal features and mitralvalve disease. In total, we assessed the prevalence of TGFB2 mutationsin 146 patients.Using direct sequencing after ampli fication of all exons and flankingintronic sequences of the TGFB2 gene on genomic DNA level (TGFB2NM_001135599.2), we identified 4 heterozygous TGFB2 mutations in 6patients: c.475C>T (p.Arg159X), c.979C>T (p.Arg327Trp), c.980G>A(p.Arg327Gln), and c.1125delT (p.Gly376GlufsX17). We found 2 prema-turetruncatingmutationsandalsoidenti fiedthe firstmissensemutationsin TGFB2. All mutations are expected to result in a loss-of-function. Anoverview of the clinical findings is provided in Table 1 and of the muta-tions in Fig. 1 and Supplemental Table 1.Aortic pathology was universally present at middle-age (z-scores >2.5),butaorticdissectionwasthepresentingfeatureinonlyonepatientat the age of 69 years (patient 1). Importantly, type A dissection oc-curredinanotherpatient5 yearsafterinitialevaluationandatanaorticroot diameter below the classical surgical threshold of 50 mm (patient6). Significant mitral valve prolapse occurred in 4 patients and was thereasonforinitialevaluationintwopatients(2and6)thatbothrequiredsurgical replacement. Patient 4 came to medical attention following aroutine echocardiography showing aortic root dilatation and mitralvalve prolapse without other manifestations. One patient (patient 3)was evaluated following transient ischemic attacks at the age of18 yearsoldwithunderlyingtortuosityofthevertebralarteries.Finally,patient 5 was evaluated for skeletal marfanoid features.Fouroutof6 patientshadskeletaland/orskinmanifestationsrem-iniscent of TGFβ-signalopathies which can be mild; 3 patients hadmyopia of which one had cataract. Importantly, family history wasnegative in 3 patients.Our data indicate a prevalence of TGFB2 mutations in the exam-ined TAAD cohort of around 4% (6/146), which is significantly lowerthan the previously reported prevalence of ACTA2 mutations (16%)[11]. The TGFβ superfamily includes 3 isoforms of TGFβ, TGFβ1, −2,and −3 (for a review [12]). The TGFβs are pleiotropic cytokines, con-trolling a broadrange of biologicalprocesses. The3 TGFβ isoforms ex-hibit both overlapping and divergent properties as illustrated by thephenotype of the respective knockout mouse models. Tgfb2 knockoutmice die perinatally and display a wide range of developmental de-fects, including cardiovascular, pulmonary, skeletal, ocular, inner ear