This report describes a syndromic developmental disorder that, based on whole genome sequencing (WGS) and whole-exome sequencing (WES) analyses, has been associated with the human gene TBX2. This disorder exhibits autosomal dominant inheritance, possibly with incomplete penetrance. TBX2 encodes a member of a family of proteins with a common DNA-binding domain, the T-box; T-box genes encode transcription factors involved in the regulation of diverse developmental processes. There is a single closely related ortholog in Drosophila, Dmel\bi, for which loss-of-function mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\bi is also closely related the the human gene TBX3.
Multiple UAS constructs of the human Hsap\TBX2 gene have been introduced into flies, including wild-type and variant forms postulated to be associated with disease. Heterologous rescue of a bi loss-of-function mutation was attempted, but was unsuccessful; the wild-type Drosophila bi gene driven by the same GAL4 driver was similarly unable to rescue the same loss-of-function mutation. Since a large genomic transgenic construct that includes the region of the bi gene does rescue loss-of-function alleles, aspects of bi expression not recapitulated in the GAL4/UAS experiments appear to be critical; bi is known to be highly sensitive to dosage.
Over-expression assays were used to assess effects of the disease-associated variants. Results are consistent with both tested variants being partial loss-of-function alleles. Variant(s) implicated in human disease tested (as transgenic human gene, TBX2): the R20Q and R305H variant forms have been introduced into flies.
Animals homozygous for loss-of-function alleles of Dmel\bi typically die during the pupal stage. Less severe mutations survive to adulthood, but exhibit defects of optomotor responses and various aspects of neurophysiology. Multiple genetic interactions have been described for Dmel\bi; see the bi gene report.
[updated Aug. 2018 by FlyBase; FBrf0222196]
[VERTEBRAL ANOMALIES AND VARIABLE ENDOCRINE AND T-CELL DYSFUNCTION; VETD](https://omim.org/entry/618223)
[T-BOX TRANSCRIPTION FACTOR 2; TBX2](https://omim.org/entry/600747)
Patients exhibit an overlapping and variable spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments; this spectrum of pathologies overlaps that of DiGeorge syndrome(FBrf0239379).
Most of the phenotypes of DiGeorge syndrome (caused by heterozygous deficiency) are associated with haploinsufficiency of the TBX1 gene (MIM:188400).
Vertebral anomalies and variable endocrine and T-cell dysfunction is a syndrome characterized by an overlapping spectrum of features. Skeletal malformations primarily involve the vertebrae, and endocrine abnormalities involving parathyroid hormone, growth hormone, and the thyroid gland have been reported. T-cell abnormalities have been observed, with some patients showing thymus gland aplasia or hypoplasia. Patients have mild craniofacial dysmorphism, and some show developmental delay or behavioral problems. Cardiac defects may be present (Liu et al., 2018; pubmed: 29726930). [from MIM:618223; 2019.03.14]
Heterozygous variants in TBX2 have been identified in 4 individuals from 2 unrelated families. Some disease-associated variants may exhibit incomplete penetrance (FBrf0239379).
Vertebral anomalies and variable endocrine and T-cell dysfunction (VETD) is caused by heterozygous mutation in the TBX2 gene.
TBX2 encodes a member of a phylogenetically conserved family of proteins with a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. TBX2 is involved in the transcriptional regulation of genes required for mesoderm differentiation and probably plays a role in limb pattern formation. [Gene Cards, TBX2; 2018.08.30]
Many to many: multiple in both species; TBX2 is most closely related the Dmel\bi.
High-scoring ortholog of human TBX2 and TBX3 (multiple in both species). Dmel\bi is most closely related to TBX2 and TBX3; it shares 37-38% identity and 46-47% similarity with these genes.
