Aneurysms-osteoarthritis syndrome (AOS), also known as Loyes-diets III, is a recently delineated autosomal dominant disorder characterized by aneurysms or dissections of large arteries, early onset osteoarthritis, craniofacial features, and skeletal anomalies. Previous studies have demonstrated that AOS is caused by mutations in SMAD3, a key regulator of TGF-β signal transduction. Here, we present the first Korean familial cases of AOS diagnosed by targeted exome sequencing. An 8 year-old boy was referred from department of orthopedic surgery for genetic evaluation of familial skeletal deformities. He had craniofacial abnormalities including hypertelorism, maloclusion, and strabismus. He also had deformities of hand joint and flat feet. His 40-year old mother also had similar facial feature and suffered from progressive severe osteoarthritis in multiple joints since her twenties. We performed targeted exome sequencing for molecular diagnosis when he was 16 years old. Targeted exome sequencing for skeletal dysplasia identified a novel heterozygous c.1267A＞C (p.Ser423Arg) mutation in SMAD3, which was also found in his mother but not present in unaffected father and elder brother. After diagnosis of AOS, we performed cardiac evaluation although they were asymptomatic. Cardiac echography and CT angiography revealed dilated root of ascending aorta (diameter : 6.2cm), aneurysm of asecnding aorta, moderate aortic regurgitation. He had Bentall’s operation and he has now taking warfarin. However, his mother did not have arterial aneurysm. We suggest that targeted exome sequencing could be a useful diagnostic tool for the genetic connective tissue disease presented with multi-systemic symptoms.