Identification of a deletion containing TBX4 in a neonate with acinar dysplasia by rapid exome sequencing

Abstract

We describe a neonate with severe respiratory failure due to acinar dysplasia found by rapid exome sequencing (rES), to have a deletion containing the TBX4 gene. rES can affect patient management in the intensive care unit and should be considered in concert with lung biopsy in neonates with undifferentiated respiratory failure.

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

“…Interestingly, the US PAH Biobank study confirmed a causative role of TBX4 not only across various age groups (12/266; 4.6%-paediatric-onset; 11/2345; 0.47%-adult-onset) but also across different PH phenotypes: 2 (one adult; one paediatric)/23; 8.7% PAH-CTD, 3 (two paediatric and one adult-onset)/23; 13% PAH-CHD [25]. Not all patients harbouring deleterious variants in TBX4 fit neatly into Group 1 PH, some individuals with heterozygous mutations in TBX4 or large deletions encompassing TBX4 were characterised by death in infancy secondary to acinar dysplasia [300], congenital alveolar dysplasia and pulmonary hypoplasia [301]. The studies dissecting phenotype by mutation type or looking for subtle features (i.e., SPS) among patients harbouring deleterious variants in TBX4 who were initially diagnosed with PAH are lacking.…”

A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report

“…TBX2 abnormalities have been associated with a cardiovascular and skeletal developmental disorder [25,42]. Recently, we and others have described heterozygous recurrent and nonrecurrent CNV deletions on 17q23.1q23.2, involving TBX2 and TBX4, as well as de novo heterozygous missense TBX4 variants [30][31][32][33] in patients with PH and other lethal pulmonary abnormal growth conditions. PH is a group of rare lung developmental diseases histopathologically characterized by a reduction of the number and size of bronchioles and alveoli [43,44].…”

“…Other patients with this deletion have also presented pulmonary arterial hypertension (PAH) and/or ischiocoxopodopatellar syndrome (MIM# 147891) [26][27][28][29]. Most recently, we and others have identified the heterozygous 17q23.1q23.2 CNV deletion in a series of individuals with lethal lung developmental disorders (LLDDs), including acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD), and other forms of primary pulmonary hypoplasia (PH) [30][31][32]. The same lethal lung phenotypes were found in patients with heterozygous point mutations in TBX4, indicating it is the causative gene [31][32][33].…”

TBX4 syndrome: a systemic disease highlighted by pulmonary arterial hypertension in its most severe form

“…Yet, not all of the subjects with PH and heterozygous TBX4 mutations fit neatly in the group 1 classification. In addition to the reports described above, a growing body of literature describes profound defects of lung development associated with heterozygous TBX4 mutations (or large gene deletions encompassing TBX4), including death during infancy due to acinar dysplasia, congenital alveolar dysplasia, and pulmonary hypoplasia [12][13][14][15]. This is not surprising, given the important role in development, including but not limited to the lung and skeletal system, of TBX4 and related molecular pathway members [16].…”