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.
Pande et al. (Thu,) studied this question.