Genetic screening in a large Chinese cohort of adult-onset non-surgical hypoparathyroidism.

BACKGROUND

Few epidemiological evidence is available on genetic hypoparathyroidism (HP) in adult-onset non-surgical hypoparathyroidism (ns-HP). This study aimed to investigate the spectrum of genotypes and clinical phenotypes of genetic HP in a single-center large sample of Chinese adult-onset ns-HP cohort.

METHODS

A systemic screening of HP-causing genes and clinical studies were conducted in adult-onset (age > 18 years old) ns-HP patients. Targeted next-generation sequencing/whole exome sequencing (T-NGS/WES) and multiplex ligation-dependent probe amplification (MLPA) of the TBX1 gene were performed to identify rare variants of 20 HP-causative genes. The fluorescence imaging of intracellular ionized calcium (Ca2+) experiments were conducted to identify the function of CASR with variants of uncertain significance. Clinical data were collected retrospectively and compared between patients with pathogenic/likely pathogenic (P/LP) variants and idiopathic HP (IHP).

RESULTS

A total of 97 adult-onset ns-HP patients were enrolled in the study. The detection rate of P/LP variants was 5.2% (5/97). Five HP patients were identified to carry five P/LP rare variants of four genes, including GATA3, TBX1 (n = 2), CASR, and AIRE. Three variants were newly identified in our study. The mean onset age of the five patients with P/LP variants was 37.6 ± 14.5 years. No significant differences in terms of most clinical characteristics between the P/LP group and the IHP group were found in our study.

CONCLUSIONS

Genetic factors may not be the main cause of ns-HP, and it is better to screen the common causative genes including TBX1, CASR, AIRE, and GATA3 in adult-onset ns-HP patients with a positive family history, syndromic phenotype, trend to hypercalciuria, or other hereditary signs.