First Genotype-Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease

Area of Science:

• Genetics
• Pulmonology
• Molecular Biology

Background:

• Pulmonary arterial hypertension (PAH) is increasingly linked to TBX4 (T-BOX transcription factor 4) gene variants.
• Understanding genotype-phenotype associations in TBX4-associated PAH is crucial for diagnosis and treatment.

Purpose of the Study:

• To functionally characterize all reported TBX4 variants.
• To conduct a comprehensive genotype-phenotype analysis in patients with TBX4 variants.
• To compare TBX4-associated PAH with PAH linked to BMPR2 variants or unknown genetic causes.

Main Methods:

• Assembled a multicenter cohort of 137 patients with monoallelic TBX4 variants.
• Assessed missense variant pathogenicity using a luciferase reporter assay.
• Compared patient cohorts using National Institute for Health Research BioResource-Rare Diseases data.

Main Results:

• Identified gain-of-function TBX4 variants associated with older age at diagnosis versus loss-of-function.
• TBX4 variants in T-BOX and nuclear localization domains correlated with earlier presentation and increased interstitial lung disease.
• TBX4 variant carriers were diagnosed younger with worse lung function compared to BMPR2 and idiopathic PAH groups.

Conclusions:

• TBX4 syndrome results from both haploinsufficiency and gain-of-function mechanisms.
• Differential effects of mutations in critical protein domains may explain TBX4's pleiotropic roles in lung disease.