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Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth,pulmonary hypertension,microcephaly, and spasticity |
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| Authors: | Justyna A. Karolak Przemyslaw Szafranski David Kilner Chirag Patel Bonnie Scurry Esther Kinning Kate Chandler Shalini N. Jhangiani Zeynep H. Coban Akdemir James R. Lupski Edwina Popek Paweł Stankiewicz |
| Affiliation: | 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland;2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas;3. Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, South Brisbane, Queensland, Australia The University of Queensland, Brisbane, Queensland, Australia;4. Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia;5. Pathology Queensland, Royal Brisbane and Women's Hospital and Lady Cilento Children's Hospital, Brisbane, Queensland, Australia;6. West of Scotland Regional Genetics Service, Queen Elizabeth Hospital, Glasgow, UK;7. Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK;8. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas;9. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas Texas Children's Hospital, Houston, Texas Department of Pediatrics, Baylor College of Medicine, Houston, Texas;10. Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas |
| Abstract: | The canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full-term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes. |
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