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Complex Genomic Rearrangement Involving the TBX4 Promoter Manifesting With Variable Expressivity in a Five-Generation
Shruti A Pande1, Hiuling Chan Joiner1, Przemyslaw Szafranski1
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA, bcm.edu.
Human Mutation
|August 4, 2026
Summary
A complex genomic rearrangement in the TBX4 gene causes ischiocoxopodopatellar syndrome (ICPPS) and related lung disorders. Variable expressivity may be influenced by other genetic variants affecting TBX4 expression.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Medical Genetics
Background:
- TBX4 gene variants are linked to ischiocoxopodopatellar syndrome (ICPPS), pulmonary arterial hypertension (PAH), and lung developmental issues.
- Understanding the genotype-phenotype correlations of TBX4 variants is challenging due to variable penetrance and expressivity.
Purpose of the Study:
- To investigate the genetic basis of ICPPS and related disorders in a five-generation family.
- To identify causative and modifying genetic variants associated with TBX4-related phenotypes.
Main Methods:
- Whole-genome sequencing was employed to identify genetic variants in affected individuals.
- Computational analyses were performed to assess noncoding single nucleotide variants (SNVs) in regulatory regions of TBX4.
Main Results:
- A complex genomic rearrangement (CGR) involving the TBX4 promoter and 5' untranslated region was identified and segregated within the family.
- The CGR comprises an insertion, deletion, and inversion, impacting TBX4 regulation.
- Candidate modifying SNVs were found in the TBX4 lung-specific super-enhancer and topologically associating domain (TAD), including the promoter.
Conclusions:
- The identified CGR is the likely cause of ICPPS and associated lung abnormalities in the studied family.
- Variable expressivity of the CGR may be modulated by other genetic variants acting in trans, influencing TBX4 expression from the intact allele.
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