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Open AccessArticle

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

1
Human Genetics Institute, Department of Life, Health, and Environmental Sciences, University of L'Aquila, 67100 L’Aquila, Italy
2
Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
3
Clinical Genetics Unit, Department of Pediatrics, Regional Hospital of Bolzano, 39100 Bolzano, Italy
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Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, 00185 Rome, Italy
5
San Camillo-Forlanini Hospital, 00152 Rome, Italy
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Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, 00167 Rome, Italy
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Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy
8
Medical Genetics Unit, Policlinico Tor Vergata University Hospital, 00133 Rome, Italy
9
IRCCS Neuromed Institute, 86077 Pozzilli, Italy
*
Authors to whom correspondence should be addressed.
Genes 2019, 10(10), 764; https://doi.org/10.3390/genes10100764
Received: 27 August 2019 / Revised: 17 September 2019 / Accepted: 21 September 2019 / Published: 28 September 2019
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. View Full-Text
Keywords: hereditary connective tissue disorders; Loeys-Dietz syndrome; Ehlers-Danlos syndrome; arterial aneurysms; TGFBR1; TGFBR2; SMAD2; SMAD3; TGFB2; TGFB3. hereditary connective tissue disorders; Loeys-Dietz syndrome; Ehlers-Danlos syndrome; arterial aneurysms; TGFBR1; TGFBR2; SMAD2; SMAD3; TGFB2; TGFB3.
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Camerota, L.; Ritelli, M.; Wischmeijer, A.; Majore, S.; Cinquina, V.; Fortugno, P.; Monetta, R.; Gigante, L.; Hospital, M.S.S.G.T.V.U.; Sangiuolo, F.C.; Novelli, G.; Colombi, M.; Brancati, F. Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data. Genes 2019, 10, 764.

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