Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity

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.

Persistence of persistent pulmonary hypertension of the newborn: A case of de novo TBX4 variant

“…2 TBX4 mutations are thought to cause developmental lung abnormalities due to its role in mesoderm induction and specification during fetal lung development. 2,8 Given these structural manifestations, the role of glucocorticoids in these patients is unclear, even in the setting of concurrent PIG. As glucocorticoids promote lung maturity and decrease parenchymal and airway inflammation, they may play a role in improving respiratory status in children with various etiologies of lung disease.…”

Potential interactions between the TBX4-FGF10 and SHH-FOXF1 signaling during human lung development revealed using ChIP-seq

“…Several animal studies revealed that modulation of the Wnt pathway by gene knockouts resulted in early lethality often associated with impaired respiratory development due to prevention of distal lung buds formation [ 37 ]. Recently, we also reported variants in CTNNB1 and TBX4 , encoding crucial members of the Wnt and FGF signaling, in a newborn with abnormal lung growth, PAH, severe microcephaly, and spasticity, suggesting that mutations in these genes could act synergistically resulting in a lethal respiratory failure during the neonatal period [ 38 ].…”

Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia

“…Note the short fourth and fifth rays in the feet of both parents in Family 1 and the mother in Family 2, and the wide gap between the first and second toes in both parents of Family 2. hypoplasia, and alveolar growth abnormality. [14][15][16][17]41 Of note, the F1-IV:5 fetus also showed atresia of external auditory canal. We are not aware of previous reports of abnormalities in external ear development in association with TBX4 variants or CNVs in humans or other organisms, but there are reports of deletions and/or duplications of the region containing the TBX4 gene associated with hearing loss and abnormal auricles.…”

“…13 Recently, the occurrence of rare coding TBX4 variants with putative hypomorphic non-coding mutations in one of its lung enhancers has been recognized as a cause of pediatric pulmonary hypertension and lethal lung developmental disease, which is associated with congenital heart disease, foot anomalies, and developmental disability. [14][15][16][17] T-box genes are a family of evolutionary-conserved transcription factors characterized by a shared DNA-binding domain. They have restricted spatio-temporal patterns of expression during embryogenesis, and play distinct roles during organogenesis as documented by genetic studies performed in animal models and humans.…”