TBX5 variants and cardiac phenotype: A systematic review of the literature and a novel variant
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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TBX5 variants and cardiac phenotype : A systematic review of the literature and a novel variant. / Møller Nielsen, Anne Kathrine; Dehn, Anna Maria; Hjortdal, Vibeke; Larsen, Lars Allan.
I: European Journal of Medical Genetics, Bind 68, 104920, 2024.Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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TY - JOUR
T1 - TBX5 variants and cardiac phenotype
T2 - A systematic review of the literature and a novel variant
AU - Møller Nielsen, Anne Kathrine
AU - Dehn, Anna Maria
AU - Hjortdal, Vibeke
AU - Larsen, Lars Allan
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024
Y1 - 2024
N2 - T-Box Transcription Factor 5 (TBX5) variants are associated with Holt-Oram syndrome. Holt-Oram syndrome display phenotypic variability, regarding upper limb defects, congenital heart defects, and arrhythmias. To investigate the genotype-phenotype relationship between TBX5 variants and cardiac disease, we performed a systematic review of the literature. Through the systematic review we identified 108 variants in TBX5 associated with a cardiac phenotype in 277 patients. Arrhythmias were more frequent in patients with a missense variant (48% vs 30%, p = 0.009) and upper limb abnormalities were more frequent in patients with protein-truncating variants (85% vs 64%, p = 0.0008). We found clustering of missense variants in the T-box domain. Furthermore, we present a family with atrial septal defects. By whole exome sequencing, we identified a novel missense variant p.Phe232Leu in TBX5. The cardiac phenotype included atrial septal defect, arrhythmias, heart failure, and dilated cardiomyopathy. Clinical examination revealed subtle upper limb abnormalities. Thus, the family corresponds to the diagnostic criteria of Holt-Oram syndrome. We provide an overview of cardiac phenotypes associated with TBX5 variants and show an increased risk of arrhythmias associated to missense variants compared to protein-truncating variants. We report a novel missense variant in TBX5 in a family with an atypical Holt-Oram syndrome phenotype.
AB - T-Box Transcription Factor 5 (TBX5) variants are associated with Holt-Oram syndrome. Holt-Oram syndrome display phenotypic variability, regarding upper limb defects, congenital heart defects, and arrhythmias. To investigate the genotype-phenotype relationship between TBX5 variants and cardiac disease, we performed a systematic review of the literature. Through the systematic review we identified 108 variants in TBX5 associated with a cardiac phenotype in 277 patients. Arrhythmias were more frequent in patients with a missense variant (48% vs 30%, p = 0.009) and upper limb abnormalities were more frequent in patients with protein-truncating variants (85% vs 64%, p = 0.0008). We found clustering of missense variants in the T-box domain. Furthermore, we present a family with atrial septal defects. By whole exome sequencing, we identified a novel missense variant p.Phe232Leu in TBX5. The cardiac phenotype included atrial septal defect, arrhythmias, heart failure, and dilated cardiomyopathy. Clinical examination revealed subtle upper limb abnormalities. Thus, the family corresponds to the diagnostic criteria of Holt-Oram syndrome. We provide an overview of cardiac phenotypes associated with TBX5 variants and show an increased risk of arrhythmias associated to missense variants compared to protein-truncating variants. We report a novel missense variant in TBX5 in a family with an atypical Holt-Oram syndrome phenotype.
KW - Cardiovascular
KW - Genetics
KW - Holt-Oram syndrome
KW - TBX5
U2 - 10.1016/j.ejmg.2024.104920
DO - 10.1016/j.ejmg.2024.104920
M3 - Review
C2 - 38336121
AN - SCOPUS:85184860164
VL - 68
JO - European Journal of Medical Genetics
JF - European Journal of Medical Genetics
SN - 1769-7212
M1 - 104920
ER -
ID: 383932259