TBX1 – Conotruncal Heart Malformations

TBX1 encodes a T-box transcription factor critical for pharyngeal arch and cardiac outflow tract development. Haploinsufficiency of TBX1 is well established in 22q11.2 deletion syndromes with conotruncal anomalies (PMID:9268629). In non-syndromic conotruncal heart malformations (MONDO_0016581), emerging genetic and functional data have assessed TBX1’s role outside of chromosomal deletions.

In an exome-based burden analysis of 245 patients with conotruncal defects and ultrarare protein-altering variants across 1,451 combined cases, TBX1 was one of three genes with significant enrichment compared to matched controls (PMID:36789878). This statistical association supports TBX1 involvement in isolated conotruncal anomalies.

Individual variant evidence includes a de novo missense mutation c.385G>A (p.Glu129Lys) in a patient with isolated conotruncal defects, which exhibited near-complete loss of transactivation activity in vitro (PMID:24998776). This finding underpins an autosomal dominant haploinsufficiency mechanism with pathogenic de novo occurrence.

Variant spectrum in conotruncal presentations is dominated by rare missense alleles that disrupt TBX1 function. Familial segregation data in nonsyndromic cohorts are limited (0 additional affected relatives), but de novo and ultrarare occurrence strengthen pathogenicity assertions.

Functional modeling in mouse embryos demonstrates that Tbx1 haploinsufficiency abolishes Fgf8 expression in pharyngeal endoderm and remodels the fourth arch artery, leading to outflow tract defects recapitulating human conotruncal phenotypes (PMID:12223416). Conditional and compound heterozygous mouse models further confirm dosage sensitivity and morphological concordance (PMID:21107579).

However, mutation screening of 41 nonsyndromic conotruncal cases did not identify TBX1 pathogenic variants, suggesting genetic heterogeneity and the need for larger cohorts (PMID:12700609).

Collectively, significant ultrarare variant burden in 1,451 cases, a functional de novo missense allele, and concordant animal models support a Moderate clinical validity classification for TBX1 in conotruncal heart malformations. Inclusion of TBX1 in diagnostic gene panels for conotruncal defects is warranted, focusing on rare autosomal dominant variants.

References

• Genomics • 1997 • Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene. PMID:9268629
• Journal of the American Heart Association • 2023 • Evaluating High-Confidence Genes in Conotruncal Cardiac Defects by Gene Burden Analyses. PMID:36789878
• BMC Medical Genetics • 2014 • Novel TBX1 loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion. PMID:24998776
• Development (Cambridge, England) • 2002 • A genetic link between Tbx1 and fibroblast growth factor signaling. PMID:12223416
• Mammalian Genome : official journal of the International Mammalian Genome Society • 2010 • Manipulation of endogenous regulatory elements and transgenic analyses of the Tbx1 gene. PMID:21107579
• European Journal of Human Genetics • 2003 • DiGeorge subtypes of nonsyndromic conotruncal defects: evidence against a major role of TBX1 gene. PMID:12700609

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