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A novel long-range deletion spanning STX16 and NPEPL1 causing imprinting defects of the GNAS locus discovered in a patient with autosomal-dominant pseudohypoparathyroidism type 1B

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Abstract

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.

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Acknowledgements

We thank the patient for getting permission to publish relative information.

Funding

This work was supported by the Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (CAMS-I2M) (No. 2017-I2M-1–001) and the National Natural Science Foundation of China (No. 81873641).

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Authors and Affiliations

  1. Key Laboratory of Endocrinology of the Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China

    Yi Yang, Xueying Chu, Min Nie, An Song, Yan Jiang, Mei Li, Weibo Xia, Xiaoping Xing & Ou Wang

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  1. Yi Yang
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All of the procedures performed in the study involving the human participant were approved by the Ethics Committee of Peking Union Medical College Hospital and conducted under the instructions of the principles in the Declaration of Helsinki.

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Yang, Y., Chu, X., Nie, M. et al. A novel long-range deletion spanning STX16 and NPEPL1 causing imprinting defects of the GNAS locus discovered in a patient with autosomal-dominant pseudohypoparathyroidism type 1B. Endocrine 69, 212–219 (2020). https://doi.org/10.1007/s12020-020-02304-6

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