Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.

NCCM is a heterogeneous condition, and genetic stratification has a role in clinical care. Distinguishing genetic from nongenetic NCCM complements prediction of outcome and may lead to management and follow-up tailored to genetic status.

Background-Left ventricular (LV) noncompaction (LVNC) is a distinct cardiomyopathy featuring a thickened bilayeredLV wall consisting of a thick endocardial layer with prominent intertrabecular recesses with a thin, compact epicardial layer. Similar to hypertrophic and dilated cardiomyopathy, LVNC is genetically heterogeneous and was recently associated with mutations in sarcomere genes. To contribute to the genetic classification for LVNC, a systematic cardiological family study was performed in a cohort of 58 consecutively diagnosed and molecularly screened patients with isolated LVNC (49 adults and 9 children). Methods and Results-Combined molecular testing and cardiological family screening revealed that 67% of LVNC is genetic.Cardiological screening with electrocardiography and echocardiography of 194 relatives from 50 unrelated LVNC probands revealed familial cardiomyopathy in 32 families (64%), including LVNC, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Sixty-three percent of the relatives newly diagnosed with cardiomyopathy were asymptomatic. Of 17 asymptomatic relatives with a mutation, 9 had noncompaction cardiomyopathy. Clinical Perspective on p 239Prevalence of LVNC, estimated from retrospective studies, ranges from 4.5 to 26 per 10 000 adult patients referred for echocardiography. 3-5 LVNC was diagnosed in 3.7% of patients with an LV ejection fraction Յ45%, suggesting that LVNC might not be a rare disorder in adults. 5 In pediatric series, LVNC is the most frequent cardiomyopathy after dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), comprising Ϸ9% of childhood cardiomyopathies. 6 Clinical features include heart failure, arrhythmias, and thromboembolic events. 3,7 Familial disease was estimated to occur in Ϸ18% to 50% of adults with isolated LVNC, mostly consistent with an autosomal dominant mode of inheritance. 3,8 -13 Intrafamilial phenotypic variability, including LVNC, HCM, and DCM, suggests that these cardio- and rare chromosomal defects and loci. [23][24][25][26][27][28][29][30] The present study investigates the heredity of LVNC, the spectrum of clinical features, and the genetic causes of LVNC by combining systematic cardiological family studies with extensive molecular analysis. Methods Study PopulationThe study comprised 58 unrelated patients with isolated LVNC; 53 were diagnosed consecutively from 2005 to 2008 in the cardiogenetics clinic of the Erasmus MC in Rotterdam and 5 in other tertiary referral centers in The Netherlands. All fulfilled the 4 echocardiographic diagnostic Jenni criteria: (1) excessively thickened LV myocardial wall with a 2-layered structure comprising a compact epicardial layer (C) and a noncompacted endocardial layer (NC) of prominent trabeculations and deep intertrabecular recesses; (2) maximal end-systolic ratio of noncompacted to compacted wall Ͼ2 measured at the parasternal short axis; (3) color Doppler evidence of deep perfused intertrabecular recesses; and (4) absence of coexisting Hoedemaekers et al Family Study of Noncompa...

Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium.

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients.