Endocrine Abstracts

Objective: We aimed to identify the genetic defect in patients labelled as sporadic and idiopathic hypoparathyroidism (HP) by using whole-exome sequencing (WES).

Methods: Patients with sporadic nonsurgical HP, aged <30 years were recruited. Those with a known genetic or autoimmune aetiology were excluded from the study. Thirty such patients were screened for antibodies against interferon-α, a highly sensitive and specific marker of autoimmune polyendocrine syndrome type 1 (APS1). Eight patients had an elevated titer and all of them carried double mutations in the AIRE, responsible for APS1. The remaining 22 were screened for DiGeorge syndrome via multiplex-ligand dependent probe amplification (MLPA) and five had deletions diagnostic of DiGeorge syndrome. The remaining 17 were subjected to WES. Mutations were confirmed by Sanger sequencing, and the pathogenicity of novel variants were confirmed by in-silico functional analyses.

Results: Of the 17 patients who underwent WES, pathogenic variants causing HP were detected in five (29%) patients. Patient #1 (current age 32 years, age of onset of disease 24 years) had a known pathogenic variant c. 1504A>C, Asn502His in the GCM2 gene. Patient #2 (current age 19 years, age of onset of disease at 1 month) and patient #3 (age of onset of the HP 20 years, current age 32 years) had novel mutations in the GCM2 gene; homozygous mutation c.391C>T, Arg131* and heterozygous variant c.319G>A, Asp107Asn, respectively. Patient #4 (current age 21 years, age of onset of disease 14 year) carried a heterozygous variant in exon 6 of the AIRE gene (c.739C>T, Arg247Cys). Patient #5 with HP and additional features such as sensory neural hearing loss and dysmorphic facies carried a heterozygous variant c.1608G>T (Met536lle) in the AIRE. All the novel variants were pathogenic as assessed in the in-silico functional analysis. The patients carrying the AIRE mutations did not have other endocrine and ectodermal components on further investigations.

Conclusion: Muations in the GCM2 and AIRE were common in patients with seemingly sporadic and idiopathic hypoparathyroidism. In contrast to the classic homozygous/compound heterozygous mutations in the AIRE which is responsible for childhood-onset APS1 and widespread endocrine and ectodermal manifestation, heterozygous mutations in the AIRE can manifest as isolated HP and negative for antibodies againt interferon-α. All young patients with sporadic and idiopathic hypoparathyroidism should be evaluated for genetic basis especially GCM2 and AIRE.