title: RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Urologic Surgery, The 117th PLA Hospital, Hangzhou, Zhejiang, China. qxplmd@vip.sina.com
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Qi
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Ma
authors.forename: Zhen-Fang
authors.initials: ZF
authors.lastname: Du
authors.forename: Rong-Biao
authors.initials: RB
authors.lastname: Ying
authors.forename: Jun
authors.initials: J
authors.lastname: Fei
authors.forename: Hang-Yang
authors.initials: HY
authors.lastname: Jin
authors.forename: Jian-Shan
authors.initials: JS
authors.lastname: Han
authors.forename: Jin-Quan
authors.initials: JQ
authors.lastname: Wang
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Chen
authors.forename: Chun-Yue
authors.initials: CY
authors.lastname: Chen
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liu
authors.forename: Jia-Jun
authors.initials: JJ
authors.lastname: Lu
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: Xian-Ning
authors.initials: XN
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics*; D018276:Carcinoma, Medullary / Q000151:congenital; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013964:Thyroid Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human