Holt-Oram Syndrome (HOS) via the TBX5 Gene

Holt-Oram syndrome (OMIM#142900) is a developmental disorder characterized by upper-extremity malformations involving radial, thenar, or carpal bones; congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD); or cardiac conduction disease (Newbury-Ecob et al. J Med Genet 33: 300-307, 1996). An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. HOS is the most common of the heart-hand syndromes, affecting individuals from different racial and ethnic groups.

HOS is inherited in an autosomal dominant manner with marked intra- and interfamilial variation. Approximately 85% of affected individuals have HOS as the result of de novo variants. The upper-limb malformations in HOS are fully penetrant, while congenital heart malformations occur in ~75% of affected individuals. TBX5 gene is the only gene known to be associated with HOS. The majority of reported variants are frameshift, missense, nonsense, and splice-site variants. Deletion of an exon(s) or the entire TBX5 gene was detected in <1% of HOS individuals (Borozdin et al. Hum Mutat 27:975–976, 2006). TBX5 encodes T-Box 5, a member of the T-box family of transcription factors that has an important role in both cardiogenesis and limb development (Basson et al. Nat Genet 15:30–35, 1997). Its T-box domain, which is the DNA binding region, is highly conserved across species and among members of the T-box family. Missense variants at the 5' end of the T-box tend to be associated with more serious cardiac defects; missense variants at the 3' end of the T-box result in more pronounced limb defects (Basson et al. Nat Genet 15:30–35, 1997; Brassington et al. Am J Hum Genet 73:74–85, 2003).

This test is predicted to detect disease variants in >70% of individuals who meet strict diagnostic criteria for HOS (McDermott et al. i 58:981–986, 2005). Lower variant detection rates (30%-40%) reported in some studies (Cross et al. J Med Genet 37:785–787. 2000, Brassington et al. Am J Hum Genet 73:74–85, 2003) can be explained by the inclusion in patient cohorts of subjects who may not meet strict HOS diagnostic criteria.

This test provides full coverage of all coding exons of the TBX5 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).