TY - JOUR
T1 - Phenotypic spectrum of TGFB3 disease-causing variants in a Dutch-French cohort and first report of a homozygous patient
AU - Marsili, Luisa
AU - Overwater, Eline
AU - Hanna, Nadine
AU - Baujat, Geneviève
AU - Baars, Marieke J.H.
AU - Boileau, Catherine
AU - Bonneau, Dominique
AU - Brehin, Anne Claire
AU - Capri, Yline
AU - Cheung, Ho Y.
AU - Dulfer, Eelco
AU - Gerard, Marion
AU - Gouya, Laurent
AU - Hilhorst-Hofstee, Yvonne
AU - Houweling, Arjan C.
AU - Isidor, Bertrand
AU - Le Gloan, Lauriane
AU - Menke, Leonie A.
AU - Odent, Sylvie
AU - Morice-Picard, Fanny
AU - Vanlerberghe, Clemence
AU - Voorhoeve, Els
AU - van Tintelen, J. Peter
AU - Maugeri, Alessandra
AU - Arnaud, Pauline
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype.
AB - Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype.
KW - Loeys-Dietz syndrome
KW - TGFB3
KW - aortic dilatation
KW - aortic dissection
KW - connective tissue disorder
KW - transforming growth factor beta 3
UR - http://www.scopus.com/inward/record.url?scp=85083690263&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/cge.13700
DO - https://doi.org/10.1111/cge.13700
M3 - Article
C2 - 31898322
SN - 0009-9163
VL - 97
SP - 723
EP - 730
JO - Clinical genetics
JF - Clinical genetics
IS - 5
ER -