Exome Sequencing Reveals Mutations in AIRE as a Cause of Isolated Hypoparathyroidism

Context: Most cases of autosomal recessive hypoparathyroidism (HYPO) are caused by loss-of-function mutations in GCM2 or PTH.

Objective: The objective of this study was to identify the underlying genetic basis for isolated HYPO in a kindred in which 3 of 10 siblings were affected.

Subjects: We studied the parents and the three adult affected subjects, each of whom was diagnosed with HYPO in the first decade of life.

Methods: We collected clinical and biochemical data and performed whole exome sequencing analysis on DNA from the three affected subjects after negative genetic testing for known causes of HYPO.

Results: Whole exome sequencing followed by Sanger sequencing revealed that all three affected subjects were compound heterozygous for two previously reported mutations, c.967_979delCTGTCCCCTCCGC:p.(L323SfsX51) and c.995+(3_5)delGAGinsTAT, in AIRE, which encodes the autoimmune regulator protein that is defective in autoimmune polyglandular syndrome type 1 (APS-1). Each parent carries one mutation, and all of the children of the patients are either heterozygous for one mutation or wild type. The affected sister developed premature ovarian failure, but the two affected brothers have no other features of APS-1 despite elevated serum levels of anti-interferon-α antibodies.

Conclusions: Our findings indicate that biallelic mutations in AIRE can cause isolated HYPO as well as syndromic APS-1. The presence of antibodies to interferon-α provides a highly sensitive indicator for loss of AIRE function and represents a useful marker for isolated HYPO due to AIRE mutations.