First genotype-phenotype study in TBX4 syndrome: gain-of-function mutations causative for lung disease

Abstract

RationaleDespite the increasing frequency of TBX4-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights.MethodsWe assembled a multi-center cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with PAH patients with BMPR2 causal variants (n = 162) or no identified variants in PAH associated genes (n = 741) genotyped via the NIHR BioResource - Rare Diseases (NBR).ResultsFunctional assessment of TBX4 missense variants revealed gain-(n=8) or loss-of-function effects (n=23) with a similar wide phenotypic spectrum, ranging from early-onset developmental lung disease to adult-onset PAH. Variants located in the T-BOX and nuclear localization domains associated with earlier presentation (p = 0.002) and increased incidence of interstitial lung disease (p = 0.001). Event-free survival (death or transplantation) was marginally lower in the T-BOX group (p = 0.049) with adjustment for age and sex. Carriers of TBX4 variants were diagnosed at a younger age (p < 0.001) and had worse baseline lung function (FEV1, FVC) (p < 0.001) compared to the BMPR2 and no identified causal variant groups.ConclusionsWe demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain-of-function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.

Seeing pulmonary hypertension through a paediatric lens: a viewpoint

“…Member of the T-box genes; [44,[79][80][81][82] encodes a transcription factor involved in lung development.…”