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

Am J Med Genet A. 2020 Jul;182(7):1725-1734. doi: 10.1002/ajmg.a.61635. Epub 2020 May 25.


Holt-Oram syndrome (HOS) is a rare, autosomal dominant disorder caused by heterozygous pathogenic variants in cardiac T-box transcription factor, TBX5. Classically, it is associated with upper limb malformations and variable cardiac abnormalities. Limb manifestations are considered to be invariably present, ranging in severity from limitation in movement, to triphalangeal thumbs, absent thumbs, shortened forearms, or phocomelia. Cardiac involvement is characterized by congenital heart defects, most commonly septal structural malformations, and conduction system disease. Recently, novel TBX5 variants have also been reported in association with dilated cardiomyopathy (DCM). In this context, we report eight individuals from four unrelated families, in whom pathogenic variants in TBX5 segregated with an atypical HOS phenotype. Affected individuals exhibit relatively mild skeletal features of HOS, with a predominant cardiac phenotype, which includes several individuals affected by non-ischaemic DCM. To our knowledge, these represent the first reported cases of DCM in families with skeletal features of HOS, some of whom also harbored variants previously linked to a classical HOS phenotype (p. Arg279* and p.Arg237Gln). This finding supports diverse roles of TBX5 in cardiovascular development and function, and confirms the importance of long-term cardiac surveillance for individuals affected by HOS. Furthermore, these families highlight the wide phenotypic variability of HOS, which may include comparatively mild upper limb findings in respect to cardiac manifestations.

Keywords: TBX5; Holt-Oram syndrome; dilated cardiomyopathy.

MeSH terms

  • Abnormalities, Multiple / diagnostic imaging
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Adult
  • Cardiomyopathy, Dilated / diagnostic imaging
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / pathology
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Heart / diagnostic imaging
  • Heart / physiopathology
  • Heart Defects, Congenital / diagnostic imaging
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / pathology
  • Heart Septal Defects, Atrial / diagnostic imaging
  • Heart Septal Defects, Atrial / genetics*
  • Heart Septal Defects, Atrial / pathology
  • Humans
  • Lower Extremity Deformities, Congenital / diagnostic imaging
  • Lower Extremity Deformities, Congenital / genetics*
  • Lower Extremity Deformities, Congenital / pathology
  • Male
  • Middle Aged
  • Mutation / genetics
  • Pedigree
  • Phenotype
  • T-Box Domain Proteins / genetics*
  • Upper Extremity Deformities, Congenital / diagnostic imaging
  • Upper Extremity Deformities, Congenital / genetics*
  • Upper Extremity Deformities, Congenital / pathology
  • Young Adult


  • T-Box Domain Proteins
  • T-box transcription factor 5

Supplementary concepts

  • Familial dilated cardiomyopathy
  • Holt-Oram syndrome