Novel pathogenic TGFBR1 and SMAD3 variants identified after cerebrovascular events in adult patients with Loeys-dietz syndrome

Domenico Laterza, Marco Ritelli, Andrea Zini, Marina Colombi, Maria Luisa Dell'Acqua, Laura Vandelli, Guido Bigliardi, Luca Verganti, Stefano Vallone, Chiara Vincenzi, Francesca Rosafio, Ludovico Ciolli, Olga Calabrese, Paolo Frigio Nichelli, Livio Picchetto

Research output: Contribution to journalArticlepeer-review


Introduction: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder due to heterozygous pathogenic variants in transforming growth factor beta (TGFβ) signaling-related genes. LDS types 1–6 are distinguished depending on the involved gene. LDS is characterized by multiple arterial aneurysms and dissections in addition to variable neurological and systemic manifestations. Patient 1: a 68-year-old man was admitted due to an aphasic transient ischemic attack (TIA). Brain CT-scan and CT angiography revealed a chronic and asymptomatic right vertebral artery dissection. Stroke diagnostic panel was unremarkable. His history showed mild stroke familiarity. At age of 49, he was treated for dissecting-aneurysm of the ascending aorta and started anticoagulation therapy. Seven years later, he underwent surgery for dissecting aneurysm involving aortic arch, descending-thoracic aorta, left subclavian artery, and both iliac arteries. Patient 2: a 47-year-old man presented a left hemiparesis due to right middle cerebral artery (MCA) and anterior cerebral artery (ACA) occlusion caused by right internal carotid artery (ICA) dissection after sport activity. Despite i.v. thrombolysis and mechanical thrombectomy, he developed malignant cerebral infarction and underwent decompressive hemicraniectomy. Digital subtraction angiography showed bilateral carotid and vertebral kinking, aneurysmatic dilatation on both common iliac arteries and proximal ectasia of the descending aorta. His father and his uncle died because of an ischemic stroke and a cerebral aneurysm rupture with a subarachnoid hemorrhage (SAH), respectively. Discussion: in both cases, considering the family history and the multiple dissections and aneurysms, LDS molecular analysis was performed. In patient 1, the novel NM_005902.3 (SMAD3): c.840T > G; p.(Asn280Lys) likely pathogenic variant was identified, thus leading to a diagnosis of LDS type 3. In patient 2, the novel NM_004612.2 (TGFBR1): c.1225T > G; p.(Trp409Gly) likely pathogenic variant was found, allowing for a diagnosis of LDS type 1. Conclusion: LDS is characterized by genetic and clinical variability. Our report suggests that this genetically-determined connective tissue disorder is probably underestimated, as it might firstly show up with cerebrovascular events, although mild systemic manifestations. These findings could lead to identify people at risk of severe vascular complications (i.e., through genetic consult on asymptomatic relatives), in order to perform adequate vascular assessments and follow-up to prevent complications such as stroke.

Original languageEnglish
Article number103727
JournalEuropean Journal of Medical Genetics
Issue number10
Publication statusPublished - Oct 2019


  • Arterial dissection
  • Loeys-dietz syndrome
  • SMAD3
  • Stroke
  • TGFBR1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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