학술논문
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.
Document Type
Academic Journal
Author
Yıldız Bölükbaşı E; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Karolak JA; Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland.; Szafranski P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Gambin T; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.; Murik O; Translational Genomics Lab, Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.; Zeevi DA; Translational Genomics Lab, Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.; Altarescu G; Preimplantation Genetic Unit, Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.; Stankiewicz P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Source
Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 101235741 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4833 (Electronic) Linking ISSN: 15524825 NLM ISO Abbreviation: Am J Med Genet A Subsets: MEDLINE
Subject
Language
English
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.
(© 2022 Wiley Periodicals LLC.)
(© 2022 Wiley Periodicals LLC.)