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Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients.

ABSTRACT: BACKGROUND:Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder for which 6 genes in the TGF-? pathway have been identified as causative. With the widespread use of genetic testing, the range of known clinical and genetic profiles has broadened, but these features have not been fully elucidated thus far. METHODS AND RESULTS:Using gene panel sequencing or whole exome sequencing, we identified 54 unique rare variants in LDS genes in 57 patients with thoracic aneurysms/dissections, including 27 pathogenic mutations (P?+?LP) and 27 variants of unknown significance (VUSLP?+?VUS). Genotype-phenotype correlation analysis revealed that carriers with P/LP/ VUSLP variants in TGFBR1/TGFBR2/SMAD3 genes had significantly more severe cardiovascular features (cardiovascular death/dissection) than carriers with VUSs in these 3 genes at an early age and had less favorable event-free survival. Additionally, carriers with VUS in combination with other risk factors, such as hypertension, might be prone to developing an aortic dissection, as indicated by the fact that 5/8 (62.5%) patients with VUSs in our cohort developed aortic dissections in the presence of hypertension, compared with 25.0% (3/12) in the absence of hypertension (p?=?0.047). CONCLUSIONS:To date, this was the largest cohort of LDS patients ever reported in China, and the present study expanded the known mutation and phenotypic spectra of LDS, which might help refine our knowledge of LDS.

SUBMITTER: Yang H

PROVIDER: S-EPMC6950884 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients.

Yang Hang H Ma Yanyun Y Luo Mingyao M Zhu Guoyan G Zhang Yinhui Y Li Binbin B Shu Chang C Zhou Zhou Z

Orphanet journal of rare diseases 20200108 1

<h4>Background</h4>Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder for which 6 genes in the TGF-β pathway have been identified as causative. With the widespread use of genetic testing, the range of known clinical and genetic profiles has broadened, but these features have not been fully elucidated thus far.<h4>Methods and results</h4>Using gene panel sequencing or whole exome sequencing, we identified 54 unique rare variants in LDS genes in 57 patients with thoracic aneurysms/dis ...[more]

PMID: 31915033

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Project description:BACKGROUND AND PURPOSE:Loeys-Dietz syndrome (LDS) is a recently described entity that has the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Its neuroradiologic manifestations have not been well delineated. We sought to describe the neuroradiologic features of LDS and to assess the manifestations that would warrant follow-up imaging. MATERIALS AND METHODS:Two neuroradiologists retrospectively reviewed CT angiography (CTA), MR imaging, and plain film studies related to the head and neck in 25 patients ranging from 1 to 55 years of age, all of whom had positive genetic testing and clinical characteristics of LDS. Arterial tortuosity was evaluated by subjective assessment of 2D and 3D volumetric CTA and MR angiography data. Craniosynostosis and spinal manifestations were assessed by using plain films and CT images. MR images mostly of the head were reviewed for associated findings such as hydrocephalus, Chiari malformation, etc. Clinical manifestations were collated from the electronic patient record. RESULTS:All patients had extreme arterial tortuosity, which is characteristic of this syndrome. Thirteen patients had scoliosis, 12 had craniosynostosis, 8 had intracranial aneurysms, 6 had spinal instability, 3 had dissections of the carotid and vertebrobasilar arteries, 3 had hydrocephalus, 4 had dural ectasia, 2 had a Chiari malformation, and 1 had intracranial hemorrhage as a complication of vascular dissection. CONCLUSIONS:Significant neuroradiologic manifestations are associated with LDS, predominantly arterial tortuosity. Most of the patients in this series were young and, therefore, may require serial CTA monitoring for development of intra- and extracranial dissections and aneurysms, on the basis of the fact that most of the patients with pseudoaneurysms and dissection were older at the time of imaging. Other findings of LDS such as craniosynostosis, Chiari malformation, and spinal instability may also need to be addressed.

Dataset Information

Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients.

Publications

Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients.

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