Inherited TBX4 frameshifting variants predicted to escape nonsense mediated decay in two families with variable phenotypes, including lethal lung developmental disorders

BACKGROUND: Pathogenic variants involving the transcription factor TBX4 gene have been associated with various skeletal and pulmonary abnormalities, including lethal lung developmental disorders (LLDD). METHODS: Whole-genome sequencing (WGS) with AI-powered platform for variant detection and interpretation followed by Sanger sequencing targeted variant segregation analysis were used. Reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) studies were performed to assess gene and protein expression levels, respectively. RESULTS: We describe two unrelated families with intrafamilial variability in the TBX4 phenotypic expressivity, including LLDDs. WGS analyses revealed two frameshift variants, c.1019del; p.(Arg340GlnfsTer40) in the penultimate exon and c.1167dup; p.(Arg390GlnfsTer30) in the last exon of TBX4, both predicted to escape nonsense mediated mRNA decay (NMD) and associated with highly variable phenotypes. RT-qPCR and IHC studies implied incomplete NMD in one family. CONCLUSIONS: Our data expand the phenotypic and genotypic landscape of TBX4-associated pulmonary disease to include asthma. We propose incompleteness and variability of NMD escape contributing to the observed wide phenotypic spectrum and increased risk of LLDDs.