Complex Genomic Rearrangement Involving the TBX4 Promoter Manifesting With Variable Expressivity in a Five-Generation Family.
SA, P., H, C.J., P, S., T, G., FP, E., RE, T., MJ, P., C, H., S, M., & JA, K. (2026). Complex Genomic Rearrangement Involving the TBX4 Promoter Manifesting With Variable Expressivity in a Five-Generation Family.. Human mutation. https://doi.org/10.1155/humu/7278477
SA P, H CJ, P S, T G, FP E, RE T, et al. Complex Genomic Rearrangement Involving the TBX4 Promoter Manifesting With Variable Expressivity in a Five-Generation Family.. Human mutation. 2026; doi: 10.1155/humu/7278477
SA P, H CJ, P S, et al. Complex Genomic Rearrangement Involving the TBX4 Promoter Manifesting With Variable Expressivity in a Five-Generation Family.[J]. Human mutation. 2026. DOI: 10.1155/humu/7278477.
@article{sa2026,
author = {Pande SA and Chan Joiner H and Szafranski P and Gambin T and Edenborough FP and Thompson RE and Parker MJ and Hammond C and Moledina S and Karolak JA},
title = {Complex Genomic Rearrangement Involving the TBX4 Promoter Manifesting With Variable Expressivity in a Five-Generation Family.},
journal = {Human mutation},
year = {2026},
doi = {10.1155/humu/7278477},
note = {PMID: 42549073},
}
TY - JOUR AU - Pande SA AU - Chan Joiner H AU - Szafranski P AU - Gambin T AU - Edenborough FP AU - Thompson RE AU - Parker MJ AU - Hammond C AU - Moledina S AU - Karolak JA TI - Complex Genomic Rearrangement Involving the TBX4 Promoter Manifesting With Variable Expressivity in a Five-Generation Family. T2 - Human mutation PY - 2026 DO - 10.1155/humu/7278477 AN - PMID:42549073 ER -
Variants involving TBX4 are associated with ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension (ICPPS; also known as small patella syndrome), pulmonary arterial hypertension (PAH), and lethal lung developmental disorders. The variability of penetrance and expressivity of TBX4 variants remains a prominent challenge in understanding their genotype-phenotype correlations. We investigated a five-generation family with 12 affected individuals presenting with isolated ICPPS, lung-related manifestations with features of ICPPS, and other milder abnormalities. Whole-genome sequencing was used to identify the causative and putative modifying variants. Wefound a complex genomic rearrangement (CGR) involving the TBX4 promoter and its 5 ' untranslated region that segregated in the family. This CGR consists of an ~38 bp insertion, an ~24 bp deletion, an ~2.4 kb deletion, and an ~235 bp inversion. Computational analyses in the proband's mother with pulmonary and skeletal manifestations revealed 27 candidate modifying noncoding SNVs in the TBX4 lung-specific super-enhancer and 45 SNVs within its topologically associating domain (TAD), including seven variants within the TBX4 promoter. To explain the variable expressivity of this CGR, we propose that one or more of the variants within the TBX4 lung-specific super-enhancer or TAD may act in trans with the pathogenic CGR, modulating TBX4 expression from the intact allele.