RET Germline Mutations Identified by Exome Sequencing in a Chinese Multiple Endocrine Neoplasia Type 2A-Familial Medullary Thyroid Carcinoma FamilyReport as inadecuate




RET Germline Mutations Identified by Exome Sequencing in a Chinese Multiple Endocrine Neoplasia Type 2A-Familial Medullary Thyroid Carcinoma Family - Download this document for free, or read online. Document in PDF available to download.

Background

Whole exome sequencing provides a labor-saving and direct means of genetic diagnosis of hereditary disorders in which the pathogenic gene harbors a large cohort of exons. We set out to demonstrate a suitable example of genetic diagnosis of MEN 2A-FMTC multiple endocrine neoplasia type 2-familial medullary thyroid carcinoma using this approach.

Methodology-Principal Findings

We sequenced the whole exome of six individuals from a large Chinese MEN2A-FMTC pedigree to identify the variants of the RET REarranged during Transfection protooncogene and followed this by validation. Then prophylactic or surgical thyroidectomy with modified or level VI lymph node dissection and adrenalectomy were performed for the carriers. The cases were closely followed up. Massively parallel sequencing revealed four missense mutations of RET. We unexpectedly discovered that the proband-s daughter with MEN 2A-related MTC presented a novel p.C634Y-V292M-R67H-R982C compound mutation, due to the involvement of p.C634Y in the proband with MEN 2A and p.V292M-R67H-R982C in the proband-s husband with FMTC. In the maternal origin, p.C634Y caused bilateral MTC in all 5 cases and bilateral pheochromocytoma in 2 of the 5; the earliest onset age was 28 years. In the paternal origin, one of the six p.V292M-R67H-R982C carriers presented bilateral MTC 70 years old, one only had bilateral C-cell hyperplasia 44 years, two had bilateral multi-nodules 46 and 48 years and two showed no abnormality 22 and 19 years.

Conclusions-Significance

The results confirmed the successful clinical utility of whole exome sequencing, and our data suggested that the p.C634Y-V292M-R67H-R982C mutation of RET exhibited a more aggressive clinical phenotype than p.C634Y or p.V292M-R67H-R982C, while p.V292M-R67H-R982C presented a relatively milder pathogenicity of MTC and likely predisposed to FMTC.



Author: Xiao-Ping Qi , Ju-Ming Ma, Zhen-Fang Du, Rong-Biao Ying, Jun Fei, Hang-Yang Jin, Jian-Shan Han, Jin-Quan Wang, Xiao-Ling Chen, Ch

Source: http://plos.srce.hr/



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