Abstract
BackgroundWhole 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 FindingsWe 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/SignificanceThe 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.
Highlights
The REarranged during Transfection (RET) protooncogene containing 21 exons is mapped on chromosome 10q11.2 and encodes a tyrosine kinase receptor that plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis [1,2]
We focused on nonsynonymous (NS) variants, splice acceptor, and donor site mutations (SS), anticipating that synonymous variants would be far less likely to be pathogenic
This approach could be underemployed for mutation analysis of known genes, especially those with hot-spot mutations, our case serves as a proper example of genetic diagnosis of a pathogenic gene that harbors a large myriad of exons, those without hot-spot mutational sites, such as Cornelia de Lange syndrome with causative gene NIPBL embracing 47 exons without hot-spot mutational sites [24]
Summary
The REarranged during Transfection (RET) protooncogene containing 21 exons is mapped on chromosome 10q11.2 and encodes a tyrosine kinase receptor that plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis [1,2]. Germline mutations of RET are found in multiple endocrine neoplasia type 2 (MEN 2) and Hirschsprung disease (HSCR) in an autosomal dominant pattern [3,4]. MEN 2 and HSCR are usually distinct but occasional families have been reported with both diseases [4]. Other mutations within exons 8, 10, 11, and 13 to 16 appear to account for a small percentage of FMTC families [7,9]. Emerging reports of compound RET mutations appear to show modulation of the degree of aggressiveness and the development of unusual features of MTC [13]. 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
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