Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants

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.

Familial dilated cardiomyopathy associated with pathogenic TBX5 variants: Expanding the cardiac phenotype associated with Holt–Oram syndrome

“…It is one of the most common causes of heart failure and indications for transplant worldwide, therefore warrants prompt diagnosis and close surveillance within a multidisciplinary team (Norozi et al, 2006). The clinical diagnosis of HOS can be challenging, given the interand intrafamilial variability of cardiac and skeletal manifestations (Al-Qattan & Abou Al-Shaar, 2015;Basson et al, 1994;Brassington et al, 2003;Patel et al, 2012;Vanlerberghe et al, 2019). This is illustrated by the variable "route" to diagnosis exhibited within these families, with six of our participants being diagnosed with HOS in adulthood.…”

“…This was reconsidered after an episode of intraoperative tachycardia, and a molecular diagnosis of HOS was confirmed at age 34 years. (Ross et al, 2018) ; Basson et al, 1997;Boogerd et al, 2010;Brassington et al, 2003;Bruneau et al, 1999;Li et al, 1997 (Steimle & Moskowitz, 2017), whereas missense pathogenic variants are more likely to be associated with more complex cardiac phenotypes beyond septation (Steimle & Moskowitz, 2017;Vanlerberghe et al, 2019;Zhang et al, 2015b;Zhou et al, 2015;Zhu et al, 2017 -Shaar, 2015;Basson et al, 1999;Brassington et al, 2003;Ghosh et al, 2009;Li et al, 1997). This adds further evidence against the possibility of accurate prognostication based on genotype alone in families affected by TBX5-related disorders (Al-Qattan & Abou Al-Shaar, 2015;Brassington et al, 2003;Vanlerberghe et al, 2019).…”

“…Ventricular septal defects, mitral valve prolapse, patent ductus arteriosus, pulmonary stenosis, and more complex malformations such as tetralogy of Fallot, dextrocardia, endocardial cushion defect, and left ventricular hypoplasia are also reported (Basson et al, 1994(Basson et al, , 1999Brassington et al, 2003). First degree atrioventricular block is a frequent finding, and other conduction anomalies may be present including sinus node dysfunction, second and third degree atrioventricular block, right and left bundle branch block, left axis deviation, bradycardia, and Wolff-Parkinson-White syndrome (WPW) (Jhang et al, 2015;McDermott et al, 2008;Vanlerberghe et al, 2019). Conduction abnormalities often occur in combination with a structural cardiac anomaly, but some reports estimate up to 40% of HOS cases have isolated cardiac conduction disease (Barisic et al, 2014;Brassington et al, 2003;Newbury-Ecob et al, 1996).…”

“…Other abnormalities, such as subtle malformations of the carpal bones, hypoplasia of hand, arm or shoulder muscles, or delayed bone age may only be detectable radiologically (Basson et al, 1994; Brassington et al, 2003; McDermott et al, 2005; Newbury‐Ecob et al, 1996). Additional structural malformations, including vertebral and thoracic anomalies (Brassington et al, 2003; Newbury‐Ecob et al, 1996), and pulmonary malformation such as lung hypoplasia and horseshoe lung are also described (Qin et al, 2015; Tseng et al, 2007; Vanlerberghe et al, 2019).…”

Genetic architecture of left ventricular noncompaction in adults

“…The classification of loss-of-function variants in TBX5 relies on the identification of upper limb abnormalities consistent with Holt-Oram syndrome (HOS) 16 . Although there is minimal evidence, namely, in the form of case reports, identifying LVNC in the context of TBX5 variants is mechanistically plausible given the high prevalence of other structural abnormalities, including septal and valvular defects 22 . Additional studies are required to better understand whether the association of LVNC with TBX5 variants and HOS represents a true mechanistic link or an incidental finding.…”