Hypoparathyroidism with a TBX1 variant: reconsidering genetic etiologies in the absence of 22q11.2 deletions

Abstract

Abstract Hypoparathyroidism is most commonly postsurgical, but autoimmune and genetic causes should be considered in the absence of prior neck surgery. T-box transcription factor 1 (TBX1) is a dosage-sensitive regulator of pharyngeal pouch and parathyroid development. While DiGeorge syndrome classically results from a 22q11.2 deletion, emerging evidence suggests that heterozygous TBX1 variants may cause deletion-negative, partial phenotypes with variable penetrance. We report a 25-year-old man with congenital sensorineural hearing loss who presented with chronic hypoparathyroidism after an initial hypocalcemic seizure at age 15. Autoimmune evaluation, chromosomal microarray analysis, and fluorescence in situ hybridization for 22q11.2 deletion were unremarkable. A multigene hypoparathyroidism panel identified a TBX1 c.1009G>C (p.Asp337His) heterozygous variant of uncertain significance (VUS) in exon 8 within the consensus splice site, distinct from previously reported pathogenic splice-site mutations. This variant has been variably classified as likely pathogenic and as a VUS, reflecting differences in laboratory interpretation frameworks. This case expands the phenotypic spectrum of TBX1-associated disease, demonstrating isolated hypoparathyroidism with hearing loss in the absence of 22q11.2 deletion. Identification of TBX1 variants should prompt phenotype-directed screening for associated cardiac, renal, immunologic, and audiologic defects. Family segregation analysis can provide critical evidence to support the reclassification of VUS.