Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

Abstract

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.

Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

“…Our data also identify the OFT (orthologous to the mammalian aortic root) as the main compartment affected in alk5a mutants. Interestingly, many of the phenotypes we observed are similar to defects associated with aortopathies in clinical settings, pathologies often derived from mutations in TGF-β pathway genes (Loeys et al, 2006;Matyas et al, 2006;Camerota et al, 2019). At the morphological level, we observed that alk5a mutants present a thinning of the OFT outer wall, similar to patients affected by aortic aneurysms prone to dissection (Van Puyvelde et al, 2016;Jana et al, 2019).…”

“…Here, we established, optimized, and combined functional analyses of the adult zebrafish heart using echocardiography and MRI with a morphological characterization of the cardiac compartments and adjacent vessels using µ-CT. As a proof-of-concept, we examined alk5a/tgfbr1 mutants as TGFBR1 genetic variants in humans have been associated with aortic aneurysms and diseases of the great vessels, the diagnosis of which is most often recognized in young adults (Loeys et al, 2005;Loeys et al, 2006;Matyas et al, 2006;Weerakkody et al, 2018;Camerota et al, 2019). We show that the use of this multimodal preclinical imaging strategy allows for a robust dissection of adult zebrafish cardiac phenotypes, even in the presence of high variability between samples of the same genotype.…”

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

“…This case highpoints that while molecular diagnosis in patients with a full-blown phenotype is mainly confirmatory, in those with an incomplete presentation it turns out to be fundamental, since these individuals might not be diagnosed or even be misdiagnosed. Indeed, considering the clinical overlap not only between the different EDS subtypes but also with other HCTDs [1,9,28,30,32,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], differential diagnosis is not always forthright. Differential diagnosis includes the molecularly unsolved hEDS that shares with cEDS gJHM and more than a few (muco) cutaneous signs; however, hEDS patients usually show a lower degree of scarring and skin hyperextensibility and much more striking gJHM complications [1,7,28,29,50].…”

Abdominal Symptoms and Colonic Diverticula in Marfan’s Syndrome: A Clinical and Ultrasonographic Case Control Study

“…In one subject without mutation of the FBN1 gene, a pathogenetic variant of the TGFBR2 gene (a gene involved in transforming the growth factor β (TGF-β) signaling pathway) was present; this led to a diagnosis of LDS, a genetic condition overlapping MSF in an aortic root aneurysm and risk of dissection, in skeletal features and habitus [ 23 ]. The suggested follow-up in LDS syndrome is the same as for MFS.…”

“…In eight patients (8.9%), two genetic variants were identified: A pathogenetic variant in FBN1 and another variant of uncertain significance in the COL1A2, COL5A1, or COL5A2 genes. These genes, when functionally altered, cause Ehlers–Danlos syndrome—the classic type and, on the basis of a recent study [ 23 ], could act as modifiers of phenotypes. The presence of diverticula was found in eight out of the 62 (12.9%) patients with a single mutation and in one out of eight (12.5%) patients with a double mutation ( p > 0.99).…”