Background: Pseudohypoparathyroidism (PHP) is a rare disorder characterized by hypocalcemia, hyperphosphatemia, and resistance to parathyroid hormone (PTH). According to different GNAS mutations, PHP is divided into several subtypes, among which autosomal-dominant PHP1B (AD-PHP1B) is caused by STX16 deletion and epigenetic alteration of GNAS. Although the deletion of STX16 exons 2-6 is commonly observed, other mutations involving STX16 can also result in AD-PHP1B.
Materials and methods: The clinical information of a 38-year-old male PHP patient was collected. The genomic DNA from peripheral blood cells was extracted for genetic analysis of GNAS and upstream STX16 by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and whole-exome sequencing (WES). Sanger sequencing was performed to verify the break point of the novel long-range deletion.
Results: The patient's medical history of tetany and seizure as well as laboratory examination showing hypocalcemia and elevated PTH levels indicated the diagnosis of PHP. The results of MS-MLPA showed loss of methylation of GNAS A/B:TSS-DMR and half-reduced copy number of STX16 exon 1-9, which revealed the subtype of AD-PHP1B. Furthermore, the WES study displayed a 87.5 kb missing upstream of GNAS. A 87.5 kb deletion spanning STX16 and NPEPL1 together with an insertion of 28 bp of unknown origin was verified by PCR along with Sanger sequencing.
Conclusions: A novel deletion of 87.5 kb spanning STX16 and NPEPL1 was discovered in an AD-PHP1B patient, which provides new information on molecular defects leading to AD-PHP1B.
Keywords: Autosomal-dominant pseudohypoparathyroidism type 1B; NPEPL1 gene; Novel STX16 deletion.