Complex Genomic Rearrangement Involving the TBX4 Promoter Manifesting With Variable Expressivity in a Five‐Generation Family

Abstract

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.