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Genetic diagnosis of a Chinese multiple endocrine neoplasia type 2A family through whole genome sequencing

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Abstract

Approximately 98% of patients with multiple endocrine neoplasia type 2A (MEN 2A) have an identifiable RET mutation. Prophylactic or early total thyroidectomy or pheochromocytoma/parathyroid removal in patients can be preventative or curative and has become standard management. The general strategy for RET screening on family members at risk is to sequence the most commonly affected exons and, if negative, to extend sequencing to additional exons. However, different families with MEN 2A due to the same RET mutation often have significant variability in the clinical exhibition of disease and aggressiveness of the MTC, which implies additional genetic loci exsit beyond RET coding region. Whole genome sequencing (WGS) greatly expands the breadth of screening from genes associated with a particular disease to the whole genome and, potentially, all the information that the genome contains about diseases or traits. This is presumably due to additive effect of disease modifying factors. In this study, we performed WGS on a typical Chinese MEN 2A proband and identified the pathogenic RET p.C634R mutation. We also identified several neutral variants within RET and pheochromocytoma-related genes. Moreover, we found several interesting structural variants including genetic deletions (RSPO1, OVCH2 and AP3S1, etc.) and fusion transcripts (FSIP1-BAZ2A, etc.).

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Acknowledgements

The authors thank all the patients and their families who agreed to participate in this study. This work was supported by the National Natural Science Foundation of China (81472861), the Key Project of Zhejiang Province Science and Technology Plan, China (2014C03048-1), the Key Scientific Research Project of Nanjing Military Command, China (09Z038, 10Z036), and the Medical Science and Technology Project of Zhejiang Province, China (2014KYB219).

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  1. Zhen-Fang Du, Peng-Fei Li and Jian-Qiang Zhao have contributed equally to this work.

Authors and Affiliations

  1. Department of Oncologic and Urologic Surgery, Nanjing Military Command Hospital Center for Endocrine and Metabolic Diseases, the 117th PLA Hospital, Wenzhou Medical University, 40 Jichang Road, Hangzhou, 310004, Zhejiang Province, China

    Zhen-Fang Du, Zhi-Lie Cao, Feng Li, Ju-Ming Ma & Xiao-Ping Qi

  2. XY Biotechnology Co. Ltd, 688 Bin’an Road, Hangzhou, 310051, Zhejiang Province, China

    Peng-Fei Li

  3. Department of Head and Neck Surgery, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, 310022, Zhejiang Province, China

    Jian-Qiang Zhao

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Du, ZF., Li, PF., Zhao, JQ. et al. Genetic diagnosis of a Chinese multiple endocrine neoplasia type 2A family through whole genome sequencing. J Biosci 42, 209–218 (2017). https://doi.org/10.1007/s12038-017-9686-5

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