Inherited TBX4 Frameshifting Variants Predicted To Escape Nonsense Mediated Decay in Two Families With Variable Phenotypes, Including Lethal Lung Developmental Disorders

Authors

• Shruti A Pande
• Hiuling Chan Joiner
• Przemyslaw Szafranski
• Tomasz Gambin
• Michelle Wright
• Qian Wang
• Maiah Walters
• Jan M Friedman
• Jessica Saunders
• Nicholas Avdimiretz
• Cornelius F Boerkoel
• Nahir Cortes-Santiago
• Gail Deutsch
• Pawel Stankiewicz

Language

English

Publication Date

4-30-2026

Journal

Human Genomics

DOI

10.1186/s40246-026-00974-3

PMID

42063190

PMCID

PMC13281638

PubMedCentral® Posted Date

4-30-2026

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, T-Box Domain Proteins, Female, Phenotype, Frameshift Mutation, Nonsense Mediated mRNA Decay, Pedigree, Male, Lung Diseases, Whole Genome Sequencing, Congenital alveolar dysplasia, Small patella syndrome, Variable expressivity, Premature stop codon-mediated decay, Loss-of-function, Gain-of-function

Published Open-Access

yes

Recommended Citation

Pande, Shruti A; Chan Joiner, Hiuling; Szafranski, Przemyslaw; et al., "Inherited TBX4 Frameshifting Variants Predicted To Escape Nonsense Mediated Decay in Two Families With Variable Phenotypes, Including Lethal Lung Developmental Disorders" (2026). Faculty, Staff and Students Publications. 7173.
https://digitalcommons.library.tmc.edu/baylor_docs/7173