ArticleAmerican journal of medical genetics. Part A2022
Exacerbation of mild lung disorders to lethal pulmonary hypoplasia by a noncoding hypomorphic SNV in a lung-specific enhancer in trans to the frameshifting TBX4 variant.
Article in American journal of medical genetics. Part A, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Variant Class-Specific Phenotypes and Outcomes in Pediatric TBX4-Associated Pulmonary Hypertension.Pediatric pulmonology · 2026Article
- Inherited TBX4 frameshifting variants predicted to escape nonsense mediated decay in two families with variable phenotypes, including lethal lung developmental disorders.Human genomics · 2026Article
- Multifaceted role of T-box transcription factor 4: From embryonic development to disease pathogenesis.Genes & diseases · 2026Review
- Complex Genomic Rearrangement Involving theHuman mutation · 2026Article
- Highly Variable Expressivity of a CNV Deletion Involving TBX4 in Three Deceased Siblings With Lung Developmental Disorder and Their Mildly Affected Mother and Grandfather.Clinical genetics · 2026Article
- The Glu86 Residue in TBX4 Proves Critical for Human Lung Development.American journal of medical genetics. Part A · 2025Article
- Neonatal persistent pulmonary hypertension related to a novel TBX4 mutation: case report and review of the literature.Italian journal of pediatrics · 2024Review
- A novel non-recurrent CNV deletion involving TBX4 and leaving TBX2 intact causes congenital alveolar dysplasia.Clinical genetics · 2024Article
- Variants of LRP2, encoding a multifunctional cell-surface endocytic receptor, associated with hearing loss and retinal dystrophy.Clinical genetics · 2023Article
- Molecular Function and Contribution ofAmerican journal of respiratory and critical care medicine · 2023Review
- Variable expressivity in a four-generation ACDMPV family with a non-coding hypermorphic SNV in trans to the frameshifting FOXF1 variant.European journal of human genetics : EJHG · 2022Article
- DiminishedPediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology SocietyArticle
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Authors and funding
8 authors.
Funding
Abstract
Variants involving TBX4 are associated with a wide variety of disorders, including pulmonary arterial hypertension, ischiocoxopodopatellar syndrome (ICPPS)/small patella syndrome (SPS), lethal lung developmental disorders (LLDDs) in neonates, heart defects, and prenatally lethal posterior amelia with pelvic and pulmonary hypoplasia syndrome. The objective of our study was to elucidate the wide variable phenotypic expressivity and incomplete penetrance in a three-generation family with a truncating variant in TBX4. In addition to exome and genome sequencing analyses, a candidate noncoding regulatory single nucleotide variant (SNV) within the lung-specific TBX4 enhancer was functionally tested using an in vitro luciferase reporter assay. A heterozygous frameshift variant c.1112dup (p.Pro372Serfs*14) in TBX4 was identified in patients with mild interstitial lung disease (1), bronchiolitis obliterans (1), recurrent pneumothorax (1), ICPPS/SPS (1), LLDD (2), and in unaffected individuals (4). In two deceased neonates with LLDD, we identified a noncoding SNV rs62069651-C located in trans to the mutated TBX4 allele that reduced the TBX4 promoter activity by 63% in the reporter assay. Our findings provide a functional evidence for the recently reported model of complex compound inheritance in which both TBX4 coding and in trans noncoding hypomorphic variants in the lung-specific enhancer of TBX4 contribute to LLDD.
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