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. 2022 May;188(5):1420-1425.
doi: 10.1002/ajmg.a.62656. Epub 2022 Jan 25.

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

Esra Yıldız Bölükbaşı  1 , Justyna A Karolak  2 , Przemyslaw Szafranski  1 , Tomasz Gambin  1   3 , Omer Murik  4 , David A Zeevi  4 , Gheona Altarescu  5 , Paweł Stankiewicz  1
Affiliations

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

Esra Yıldız Bölükbaşı et al. Am J Med Genet A. 2022 May.

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.

Keywords: T-box transcription factor 4; complex compound inheritance; lethal lung developmental disorders; noncoding regulatory elements; pulmonary hypoplasia.

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Conflict of interest statement

Conflict of interests The authors declare that they have no conflict of interests.

Figures

Figure 1.
Figure 1.
(A) Pedigree of the three-generation family with the segregating frameshifting TBX4 SNV c.1115dup (p. Pro373Serfs*14) depicted as an asterix and the non-coding hypomorphic SNP rs62069651-C in the putative lung enhancer region upstream to TBX4. Proband AD121 and her brother AD122 (black shade) died due to lethal pulmonary hypoplasia at the age two weeks; AD111 (gray shade) has interstitial lung disease; AD114 (circle with vertical lines) has bronchiolitis obliterans; AD115 (square with horizontal lines) has recurrent pneumothorax; AD119 (gridded square) has ischiocoxopodopatellar syndrome (ICPPS). The other family members have no abnormal lung phenotype. (B) Results of the luciferase reporter assay with the SNV rs62069651-C showing the decrease of TBX4 promoter activity by about 63% (t test P = 0.0005, compared to the common variant T.
See this image and copyright information in PMC

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