RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.

<h4>Background</h4>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 endocri...

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Autores principales:	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, Chun-Yue Chen, Wen-Ting Liu, Jia-Jun Lu, Jian-Guo Zhang, Xian-Ning Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8fc832181772457c909b0e2d2860f7de
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spelling	oai:doaj.org-article:8fc832181772457c909b0e2d2860f7de2021-11-18T06:52:52ZRET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.1932-620310.1371/journal.pone.0020353https://doaj.org/article/8fc832181772457c909b0e2d2860f7de2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21655256/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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).<h4>Conclusions/significance</h4>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.Xiao-Ping QiJu-Ming MaZhen-Fang DuRong-Biao YingJun FeiHang-Yang JinJian-Shan HanJin-Quan WangXiao-Ling ChenChun-Yue ChenWen-Ting LiuJia-Jun LuJian-Guo ZhangXian-Ning ZhangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 5, p e20353 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Chun-Yue Chen Wen-Ting Liu Jia-Jun Lu Jian-Guo Zhang Xian-Ning Zhang RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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).<h4>Conclusions/significance</h4>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.
format	article
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 Chun-Yue Chen Wen-Ting Liu Jia-Jun Lu Jian-Guo Zhang Xian-Ning Zhang
author_facet	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 Chun-Yue Chen Wen-Ting Liu Jia-Jun Lu Jian-Guo Zhang Xian-Ning Zhang
author_sort	Xiao-Ping Qi
title	RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.
title_short	RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.
title_full	RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.
title_fullStr	RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.
title_full_unstemmed	RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.
title_sort	ret germline mutations identified by exome sequencing in a chinese multiple endocrine neoplasia type 2a/familial medullary thyroid carcinoma family.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/8fc832181772457c909b0e2d2860f7de
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RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.

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