Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature

Abstract

BackgroundPathogenic SMAD3 variants are responsible for a cardiovascular phenotype, mainly thoracic aortic aneurysms and dissections. Precocious identification of the vascular risk such as aortic dilatation in mutated patients has a major impact in terms of management, particularly to avoid dissection and sudden death. These vascular damages are classically associated with premature osteoarthritis and skeletal abnormalities. However, variable expressivity and incomplete penetrance are common with SMAD3 variants.MethodsTo investigate the clinical variability observed within SMAD3 patients, we reviewed the phenotypic and genetic data of 22 new patients from our Centre and of 133 patients reported in the literature. From this cohort of 155 mutated individuals, we first aimed to delineate an estimated frequency of the main clinical signs associated with SMAD3 pathogenic variants and, then, to look for genotype‐phenotype correlations, mainly to see if the aortic phenotype (AP) could be predicted by the SMAD3 variant type.ResultsWe showed, herein, the absence of correlation between the SMAD3 variant type and the occurrence of an AP in patients.ConclusionTherefore, this report brings additional data for the genotype‐phenotype correlations of SMAD3 variants and the need to explore in more detail the effects of genetic modifiers that could influence the phenotype.

The first reported case of Loeys‐Dietz syndrome in a patient with biallelic SMAD3 variants

“…In particular, Loeys-Dietz syndrome type 3 (LDS3), originally named aneurysms-osteoarthritis syndrome because of the striking findings of early-onset osteoarthritis in the fourth decade of life and the presence of aortic and other vascular aneurysms, is typically considered milder than LDS1/2. While similar systemic manifestations can be present in LDS3 patients as compared to LDS1/2 patients, the of age of onset of vascular pathology is usually later (Chesneau et al, 2020;Schepers et al, 2018;van de Laar et al, 2011) and 34.8 years, respectively, which is nearly a decade before the onset of aortic events in LDS3 individuals (Jondeau et al, 2016). And although not seen in the MAC, aortic dilation necessitating surgical repair has been described in pediatric patients with SMAD3-related Loeys-Dietz syndrome (Chesneau et al, 2020;Fitzgerald, Bhat, Conard, Hyland, & Pizarro, 2014), with the youngest reported age of aneurysm repair at 12 months old (Wischmeijer et al, 2013).…”

“…In particular, Loeys‐Dietz syndrome type 3 (LDS3), originally named aneurysms‐osteoarthritis syndrome because of the striking findings of early‐onset osteoarthritis in the fourth decade of life and the presence of aortic and other vascular aneurysms, is typically considered milder than LDS1/2. While similar systemic manifestations can be present in LDS3 patients as compared to LDS1/2 patients, the of age of onset of vascular pathology is usually later (Chesneau et al, 2020; Schepers et al, 2018; van de Laar et al, 2011). Hostetler et al (2019) reported data from the Montalcino Aortic Consortium (MAC) indicating that of 212 individuals with SMAD3 mutations, only 37% had ever experienced an aortic event (defined as elective aortic aneurysm repair, aortic dissection, or aortic rupture) with a median age at first aortic event of 47 years.…”

“…This is in contrast to the outcomes of 441 affected individuals in the MAC with TGFBR1 or TGFBR2 variants, who had a median age of death of 28.4 and 34.8 years, respectively, which is nearly a decade before the onset of aortic events in LDS3 individuals (Jondeau et al, 2016). And although not seen in the MAC, aortic dilation necessitating surgical repair has been described in pediatric patients with SMAD3 ‐related Loeys‐Dietz syndrome (Chesneau et al, 2020; Fitzgerald, Bhat, Conard, Hyland, & Pizarro, 2014), with the youngest reported age of aneurysm repair at 12 months old (Wischmeijer et al, 2013).…”

“…LDS3 was initially named aneurysms-osteoarthritis syndrome due to striking presence of both aortic aneurysms and early-onset osteoarthritis, the latter of which distinguishes LDS3 from other subtypes of LDS (van de Laar et al, 2011). The phenotype of LDS3 can be milder than that caused by TGFBR1 and TGFBR2 mutations, with lower prevalence of skeletal manifestations and later onset of aortic and arterial disease, although a spectrum of disease has been reported (Chesneau et al, 2020;Hostetler et al, 2019;Schepers et al, 2018). Until 2020, all described cases of LDS were the result of heterozygous pathogenic variants in one of the six aforementioned genes of the TGF-β signaling pathway (Marsili et al, 2020;Mégarbané et al, 2020).…”

Identification of novel splice mutation in SMAD3 in two Cypriot families with nonsyndromic thoracic aortic aneurysm. Two case reports

“…As a result, it is generally accepted that SMAD3 variants are characterized by inter‐ and intra‐familial variability in phenotypic expression in addition to incomplete penetrance. Moreover, some patients present vascular aneurysms or dissections of small arteries without an aortic phenotype (Chesneau et al., 2020; Hostetler et al, 2019). The absence of complete arterial tree imaging in some of our patients makes characterization of a definitive clinical phenotype rather difficult.…”