TBX3 and TBX5 duplication: A family with an atypical overlapping Holt-Oram/ulnar-mammary syndrome phenotype

Eur J Med Genet. 2021 Jul;64(7):104213. doi: 10.1016/j.ejmg.2021.104213. Epub 2021 Apr 27.


Holt-Oram syndrome (HOS) is a rare, autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. A wide spectrum of TBX5 mutations have been reported previously, most resulting in a null allele leading to haploinsufficiency. TBX5 gene duplications have been previously reported in association with typical and atypical HOS phenotypes. Ulnar-Mammary syndrome (UMS) is a distinct rare, autosomal dominant condition caused by mutations in the TBX3 gene. TBX5 and TBX3 are physically linked in cis on human chromosome 12 and contiguous chromosome 12q24 deletions comprising both TBX5 and TBX3 genes have been previously reported but to our knowledge, duplications have never been described. We report on a large German family with at least 17 affected individuals over 6 generations bearing a duplication at 12q24.21 identified on array-CGH comprising both TBX5 and TBX3 genes. Affected patients are presenting with HOS and UMS symptoms, consisting of variable limb anomalies involving the radial and the ulnar rays and cardiac findings such as congenital heart defects, persistent arterial duct or aortic stenosis, and non-classical symptoms, such as supernumerary nipples and cardiomyopathy. Fluorescence in situ hybridisation confirmed a tandem duplication at the 12q24.21 locus. This is the first report of a contiguous TBX3/TBX5 duplication associated with HOS/UMS phenotype.

Keywords: Contiguous duplication; Holt-oram syndrome; TBX3 and TBX5 duplication; Ulnar-mammary syndrome.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Breast Diseases / complications
  • Breast Diseases / genetics*
  • Breast Diseases / pathology
  • Female
  • Gene Duplication
  • Heart Defects, Congenital / complications
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / pathology
  • Heart Septal Defects, Atrial / complications
  • Heart Septal Defects, Atrial / genetics*
  • Heart Septal Defects, Atrial / pathology
  • Humans
  • Lower Extremity Deformities, Congenital / complications
  • Lower Extremity Deformities, Congenital / genetics*
  • Lower Extremity Deformities, Congenital / pathology
  • Male
  • Pedigree
  • Phenotype*
  • T-Box Domain Proteins / genetics*
  • Ulna / abnormalities*
  • Ulna / pathology
  • Upper Extremity Deformities, Congenital / complications
  • Upper Extremity Deformities, Congenital / genetics*
  • Upper Extremity Deformities, Congenital / pathology


  • T-Box Domain Proteins
  • T-box transcription factor 5
  • TBX3 protein, human

Supplementary concepts

  • Holt-Oram syndrome
  • Ulnar-mammary syndrome