A Novel TBX1 Variant Causing Hypoparathyroidism and Deafness

Abstract

Background The TBX1 gene encodes the T-box 1 protein that is a transcription factor involved in development. Haploinsufficiency of the TBX1 gene is reported to cause features similar to DiGeorge syndrome. The TBX1 gene is located within the DiGeorge syndrome region, and studies support that the TBX1gene is responsible for most of the features of the phenotype of hemizygous deletion of chromosome 22q11.2. In this study, we report a family of 4 (a father with 3 children) who presented with congenital hypoparathyroidism and hypocalcemia, facial asymmetry, deafness, normal intelligence, and no cardiac involvement. Methods We performed whole genome sequencing, computational structural analysis of the mutants, and gene expression studies for all affected family members. Results Whole genome sequencing revealed a paternal inherited novel heterozygous variant, c.1158_1159delinsT p.(Gly387Alafs*73), in the exon 9 isoform C TBX1 gene, causing a loss of nuclear localization sequence (NLS) and transactivation domain (TAD) with no change in gene expression and resulted in a DiGeorge-like phenotype. Conclusion A pathogenic variant in the TBX1 gene exon 9 C that predicted to cause a loss in the NLS region and most of TAD leads to variable features of hypoparathyroidism, distinctive facial features, deafness, and no cardiac involvement. In addition, our report and previous reports indicate the presence of a wide phenotypic spectrum of TBX1 genetic variants and the consistent absence of cardiac involvement in the case of pathogenic variants on exon 9 isoform C TBX1 gene.

Genetics of monogenic disorders of calcium and bone metabolism

“…20,85 Although the microdeletion typically results in the loss of 30-40 genes, the majority of DGS type 1 clinical features are thought to be due to the loss of the T-Box Transcription Factor 1 (TBX1) gene, involved in parathyroid and thymus development. 20,86 A more severe DGS phenotype with marked cognitive impairment is reported in association with a chromosomal deletion on chromosome 10p (DGS type 2) and may be due to the loss of the NEBL gene. 87 Genetic testing for DGS is indicated in those with relevant clinical features including HP in infancy or childhood.…”

“…The majority of DGS cases are sporadic resulting from a de novo heterozygous 0.25–3 Mb microdeletion involving chromosome 22q11.2 (DGS type 1), although it is inherited from an affected parent in ~10% of cases 20,85 . Although the microdeletion typically results in the loss of 30–40 genes, the majority of DGS type 1 clinical features are thought to be due to the loss of the T‐Box Transcription Factor 1 ( TBX1 ) gene, involved in parathyroid and thymus development 20,86 . A more severe DGS phenotype with marked cognitive impairment is reported in association with a chromosomal deletion on chromosome 10p (DGS type 2) and may be due to the loss of the NEBL gene 87 .…”

Inborn errors of thymic stromal cell development and function

“…Dominant variants in TBX1 are a rare monogenic cause of DGS [62][63][64][65][66]. TBX1 is a member of the highly conserved Tbox family of transcriptional regulators that play important roles in varied aspects of embryonic development.…”

“…The reported mutations span exons 3–8, and specifically exon 9C, but not 9A or 9B. There is no clear genotype-phenotype correlation, except for mutations in exon 9C consistently being found in patients without CHD [ 62 , 63 , 65 ]. Variable penetrance is reported, likely because of modifier genes and epigenetic differences influencing TBX1 expression levels [ 68 ].…”

Advances in the molecular genetics of parathyroid tumors

“…[9] TBX1 is a developmentally relevant gene, and deletion of TBX1 during embryonic development can lead to hypoparathyroidism. [10] Signi cantly reduced TBX1 expression was also found in parathyroid adenomas and carcinomas. It was also found that TBX1 expression may be regulated by para bromin.…”