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.
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References
van der Linde D, Konings EEM, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58:2241–7.
Holt M, Oram S. Familial heart disease with skeletal malformations. Br Heart J. 1960;22:236–42.
Elek C, Vitéz M, Czeizel E. Holt-Oram syndrome. Orv Hetil. 1991;132:73–74. 77–78
Smith AT, Sack GH, Taylor GJ. Holt-Oram syndrome. J Pediatr. 1979;95:538–43.
Hurst JA, Hall CM, Baraitser M. The Holt-Oram syndrome. J Med Genet. 1991;28:406–10.
Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID. Holt-Oram syndrome: a clinical genetic study. J Med Genet. 1996;33:300–7.
Basson CT, Cowley GS, Solomon SD, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med. 1994;330:885–91.
Brassington A-ME, Sung SS, Toydemir RM, et al. Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am J Hum Genet. 2003;73:74–85.
Borozdin W, Bravo Ferrer Acosta AM, Bamshad MJ, et al. Expanding the spectrum of TBX5 mutations in Holt-Oram syndrome: detection of two intragenic deletions by quantitative real time PCR, and report of eight novel point mutations. Hum Mutat. 2006;27:975–6.
Barisic I, Boban L, Greenlees R, et al. Holt Oram syndrome: a registry-based study in Europe. Orphanet J Rare Dis. 2014;9:156.
Heinritz W, Moschik A, Kujat A, et al. Identification of new mutations in the TBX5 gene in patients with Holt-Oram syndrome. Heart Br Card Soc. 2005;91:383–4.
Li QY, Newbury-Ecob RA, Terrett JA, et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997;15:21–29.
Basson CT, Bachinsky DR, Lin RC, et al. Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997;15:30–35.
Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE. T-box genes in vertebrate development. Annu Rev Genet. 2005;39:219–39.
Bruneau BG, Logan M, Davis N, et al. Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Dev Biol. 1999;211:100–8.
Greulich F, Rudat C, Kispert A. Mechanisms of T-box gene function in the developing heart. Cardiovasc Res. 2011;91:212–22.
Hasson P, DeLaurier A, Bennett M, et al. Tbx4 and Tbx5 acting in connective tissue are required for limb muscle and tendon patterning. Dev Cell. 2010;18:148–56.
Cross SJ, Ching YH, Li QY, et al. The mutation spectrum in Holt-Oram syndrome. J Med Genet. 2000;37:785–7.
McDermott DA, Bressan MC, He J, et al. TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res. 2005;58:981–6.
Debeer P, Race V, Gewillig M, Devriendt K, Frijns J-P. Novel TBX5 mutations in patients with Holt-Oram syndrome. Clin Orthop. 2007;462:20–26.
Ellis DG. Chest wall deformities. Pediatr Rev. 1989;11:147–51.
Bickley SRB, Logan MPO. Regulatory modulation of the T-box gene Tbx5 links development, evolution, and adaptation of the sternum. Proc Natl Acad Sci USA. 2014;111:17917–22.
Weinstein SL, Dolan LA, Cheng JCY, Danielsson A, Morcuende JA. Adolescent idiopathic scoliosis. Lancet Lond Engl. 2008;371:1527–37.
Tseng Y-R, Su Y-N, Lu FL, et al. Holt-Oram syndrome with right lung agenesis caused by a de novo mutation in the TBX5 gene. Am J Med Genet A. 2007;143A:1012–4.
Qin X, Wei W, Fangqi G. Horseshoe lung associated with Holt-Oram syndrome. Iran J Pediatr. 2015;25:e251.
Böhm J, Heinritz W, Craig A, et al. Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein. BMC Med Genet. 2008;9:88.
Arora R, Metzger RJ, Papaioannou VE. Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system. PLoS Genet. 2012;8:e1002866.
Boogerd CJJ, Dooijes D, Ilgun A, et al. Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome. Cardiovasc Res. 2010;88:130–9.
Barnett P, Postma AV. Molecular genetics of Holt-Oram syndrome. In: John Wiley & Sons Ltd (ed). eLS. Wiley, Chichester, 2014. http://doi.wiley.com/10.1002/9780470015902.a0024329. Accessed 31 May 2016.
Al-Qattan MM, Abou Al-Shaar H. Molecular basis of the clinical features of Holt-Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications. Gene. 2015;560:129–36.
Borozdin W, Wright MJ, Hennekam RCM, et al. Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum. J Med Genet. 2004;41:e102.
Al-Baradie R, Yamada K, St Hilaire C, et al. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet. 2002;71:1195–9.
Koshiba-Takeuchi K, Takeuchi JK, Arruda EP, et al. Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nat Genet. 2006;38:175–83.
Terrett JA, Newbury-Ecob R, Cross GS, et al. Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q. Nat Genet. 1994;6:401–4.
Spielmann M, Mundlos S. Looking beyond the genes: the role of non-coding variants in human disease. Hum Mol Genet. 2016;25:R157–R165.
Smemo S, Campos LC, Moskowitz IP, Krieger JE, Pereira AC, Nobrega MA. Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Hum Mol Genet. 2012;21:3255–63.
Minguillon C, Nishimoto S, Wood S, Vendrell E, Gibson-Brown JJ, Logan MPO. Hox genes regulate the onset of Tbx5 expression in the forelimb. Dev Camb Engl. 2012;139:3180–8.
Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010;24:101–22.
VanderMeer JE, Ahituv N. cis-regulatory mutations are a genetic cause of human limb malformations. Dev Dyn Publ Am Assoc Anat. 2011;240:920–30.
Kozma C. Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet. 2001;98:168–75.
Mohd Yunos H, Green A. Fetal valproate syndrome: the Irish experience. Ir J Med Sci. 2018;187:965–8
Carli D, Garagnani L, Lando M, et al. VACTERL (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, cardiac defects, renal and limb anomalies) association: disease spectrum in 25 patients ascertained for their upper limb involvement. J Pediatr. 2014;164:458–462.
Kohlhase J, Taschner PE, Burfeind P, et al. Molecular analysis of SALL1 mutations in Townes-Brocks syndrome. Am J Hum Genet. 1999;64:435–45.
Hall JG. Thrombocytopenia and absent radius (TAR) syndrome. J Med Genet. 1987;24:79–83.
Albers CA, Paul DS, Schulze H, et al. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet. 2012;44:435–9, S1–2.
Petit F, Escande F, Jourdain AS, et al. Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause. Clin Genet. 2014;86:246–51.
Wiedemann HR, Drescher J. LADD syndrome: report of new cases and review of the clinical spectrum. Eur J Pediatr. 1986;144:579–82.
Rohmann E, Brunner HG, Kayserili H, et al. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006;38:414–7.
Vega H, Waisfisz Q, Gordillo M, et al. Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nat Genet. 2005;37:468–70.
Vega H, Trainer AH, Gordillo M, et al. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome. J Med Genet. 2010;47:30–37.
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We greatly thank all the clinicians, the patients and their families for their contribution to this study.
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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 27, 360–368 (2019). https://doi.org/10.1038/s41431-018-0303-3
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DOI: https://doi.org/10.1038/s41431-018-0303-3
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