TBX5 – Holt-Oram Syndrome

Holt-Oram syndrome (HOS) is a congenital heart-hand disorder caused by heterozygous mutations in TBX5, a T-box transcription factor essential for cardiac septation and upper limb development (PMID:8988165). ClinGen classifies the TBX5–HOS association as Definitive based on over 100 unrelated patients, multi-generation familial segregation, and concordant functional data demonstrating haploinsufficiency.

Genetic Evidence

HOS is inherited in an autosomal dominant manner with full penetrance. More than 108 distinct TBX5 variants have been reported in over 277 patients, including missense, nonsense, frameshift, splice-site, and intragenic duplications (PMID:38336121). Segregation analyses in large pedigrees, such as a five-generation family with a 48 kb exon 2–9 duplication in nine affected individuals, further support pathogenicity (PMID:22333898). A canonical variant, c.710G>A (p.Arg237Gln), has been repeatedly observed in HOS families and disrupts DNA binding (PMID:8988165).

Segregation

Segregation studies report at least eight additional affected relatives carrying pathogenic TBX5 alleles in single families, underscoring familial cosegregation and variable expressivity (PMID:22333898).

Functional Evidence

TBX5 haploinsufficiency is the primary disease mechanism. Tbx5(+/–) mice exhibit heart septal defects and conduction abnormalities mirroring HOS (PMID:11572777). Zebrafish heartstrings mutants lacking tbx5 display pectoral fin absence and cardiomyopathy (PMID:12223419). In vitro assays demonstrate that missense mutations such as G80R and R237Q impair DNA binding, reduce synergy with NKX2-5 and GATA4, and alter nuclear localization (PMID:12499378).

Integration

Collectively, the extensive case series, robust segregation data, and concordant in vivo and in vitro functional studies meet and exceed ClinGen criteria for a Definitive gene-disease relationship. No compelling conflicting evidence has been reported.

Key Take-home: TBX5 mutational analysis is clinically actionable for definitive diagnosis of Holt-Oram syndrome and informs genetic counseling and prenatal decision-making.

References

• Nature Genetics | 1997 | Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome PMID:8988165
• European Journal of Human Genetics | 2012 | TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype PMID:22333898
• Cell | 2001 | A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease PMID:11572777
• The Journal of Biological Chemistry | 2003 | Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome PMID:12499378
• Hong Kong Medical Journal | 2008 | Prenatal sonographic diagnosis of familial Holt-Oram syndrome associated with type B interrupted aortic arch PMID:18685167

Evidence Based Scoring (AI generated)