Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder

Abstract

The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Bioinformatics analyses indicate that these variants are rare and predict them to be damaging. In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2. Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles. Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder.

IRF2BPL Is Associated with Neurological Phenotypes

“…Experiments in fruit flies have previously provided experimental support in identifying causal variants for human disease, 19,54-56 and these approaches have been an integral part of the UDN. 13,14,16,21,57 The fly ortholog of IRF2BPL is a poorly characterized gene, CG11138. This gene was studied in the context of epigenetic regulation through biochemical methodologies during embryogenesis and was named pits (protein interacting with Ttk69 and Sin3A).…”

Loss-of-function in IRF2BPL is associated with neurological phenotypes

“…Experiments in fruit flies have previously provided experimental support in identifying causal variants for human disease 19,53-55 and these approaches have been an integral part of the UDN. 13,14,16,21,56 The fly ortholog of IRF2BPL is a poorly characterized gene, CG11138 . This gene was studied in the context of epigenetic regulation through biochemical methodologies during embryogenesis, and was named pits ( protein interacting with Ttk69 and Sin3A ).…”

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

“…Interestingly, there are also reports presenting overlapping features of these two syndromes in patients with contiguous deletion of both TBX3 and TBX5 [41]. 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.…”