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Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants.
Eur J Hum Genet. 2019 03; 27(3):360-368.EJ

Abstract

Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.

Authors+Show Affiliations

CHU Lille, Clinique de Génétique, 59000, Lille, France. clemence.vanlerberghe@chru-lille.fr. Univ. Lille, RADEME, EA 7364, 59000, Lille, France. clemence.vanlerberghe@chru-lille.fr.Univ. Lille, RADEME, EA 7364, 59000, Lille, France. CHU Lille, Institut de Biochimie et Génétique Moléculaire, 59000, Lille, France.CHU Lille, Clinique de Génétique, 59000, Lille, France. Univ. Lille, RADEME, EA 7364, 59000, Lille, France.Univ. Lille, RADEME, EA 7364, 59000, Lille, France.CHU Lille, Unité de chirurgie orthopédique infantile, 59000, Lille, France.Hôpital privé de La Louvière, unité de cardiologie pédiatrique, Lille, France.Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Lille, France.Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Lille, France.CHU Lille, Institut de Biochimie et Génétique Moléculaire, 59000, Lille, France.Service de Génétique, U781, Fondation Imagine, Hôpital Necker-Enfants malades AP-HP, Paris, France.Univ. Lille, RADEME, EA 7364, 59000, Lille, France. CHU Lille, Institut de Génétique Médicale, 59000, Lille, France.Univ. Lille, RADEME, EA 7364, 59000, Lille, France. CHU Lille, Institut de Biochimie et Génétique Moléculaire, 59000, Lille, France.CHU Lille, Clinique de Génétique, 59000, Lille, France. Univ. Lille, RADEME, EA 7364, 59000, Lille, France.CHU Lille, Clinique de Génétique, 59000, Lille, France.

Pub Type(s)

Journal Article
Multicenter Study

Language

eng

PubMed ID

30552424

Citation

Vanlerberghe, Clémence, et al. "Holt-Oram Syndrome: Clinical and Molecular Description of 78 Patients With TBX5 Variants." European Journal of Human Genetics : EJHG, vol. 27, no. 3, 2019, pp. 360-368.
Vanlerberghe C, Jourdain AS, Ghoumid J, et al. Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants. Eur J Hum Genet. 2019;27(3):360-368.
Vanlerberghe, C., Jourdain, A. S., Ghoumid, J., Frenois, F., Mezel, A., Vaksmann, G., Lenne, B., Delobel, B., Porchet, N., Cormier-Daire, V., Smol, T., Escande, F., Manouvrier-Hanu, S., & Petit, F. (2019). Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants. European Journal of Human Genetics : EJHG, 27(3), 360-368. https://doi.org/10.1038/s41431-018-0303-3
Vanlerberghe C, et al. Holt-Oram Syndrome: Clinical and Molecular Description of 78 Patients With TBX5 Variants. Eur J Hum Genet. 2019;27(3):360-368. PubMed PMID: 30552424.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants. AU - Vanlerberghe,Clémence, AU - Jourdain,Anne-Sophie, AU - Ghoumid,Jamal, AU - Frenois,Frédéric, AU - Mezel,Aurélie, AU - Vaksmann,Guy, AU - Lenne,Bruno, AU - Delobel,Bruno, AU - Porchet,Nicole, AU - Cormier-Daire,Valérie, AU - Smol,Thomas, AU - Escande,Fabienne, AU - Manouvrier-Hanu,Sylvie, AU - Petit,Florence, Y1 - 2018/12/14/ PY - 2018/03/08/received PY - 2018/10/25/accepted PY - 2018/10/12/revised PY - 2020/03/01/pmc-release PY - 2018/12/16/pubmed PY - 2019/5/21/medline PY - 2018/12/16/entrez SP - 360 EP - 368 JF - European journal of human genetics : EJHG JO - Eur. J. Hum. Genet. VL - 27 IS - 3 N2 - Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients. SN - 1476-5438 UR - https://www.unboundmedicine.com/medline/citation/30552424/Holt_Oram_syndrome:_clinical_and_molecular_description_of_78_patients_with_TBX5_variants_ L2 - http://dx.doi.org/10.1038/s41431-018-0303-3 DB - PRIME DP - Unbound Medicine ER -