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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing

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Carvalho, Rafael A. [1] ; Urtremari, Betsaida [1] ; Jorge, Alexander A. L. [1] ; Santana, Lucas S. [1] ; Quedas, Elisangela P. S. [1] ; Sekiya, Tomoko [1] ; Longuini, Viviane C. [1] ; Montenegro, Fabio L. M. [2] ; Lerario, Antonio M. [3] ; Toledo, Sergio P. A. [1, 4] ; Marx, Stephen J. [1, 5] ; Toledo, Rodrigo A. [6] ; Lourenco Jr, Delmar M.
Total Authors: 13
Affiliation:
[1] Univ Sao Paulo, Disciplina Endocrinol, Lab Endocrinol Celular & Mol LIM 25, Hosp Clin HCFMUSP, Fac Med, UEG, Sao Paulo, SP - Brazil
[2] Univ Sao Paulo, Disciplina Cirurgia Cabeca & Pescoco, Lab Cirurgia Vasc & Cabeca & Pescoco LIM 28, Hosp Clin HCFMUSP, Fac Med, Unidade Paratireoide, Sao Paulo, SP - Brazil
[3] Univ Michigan, Dept Internal Med Endocrinol & Diabet, Div Metab, Ann Arbor, MI 48109 - USA
[4] Fed Univ Sao Paulo UNIFESP, Endocrinol Div, Sao Paulo - Brazil
[5] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Endocrinol, Bethesda, MD - USA
[6] Vall dHebron Inst Oncol, Barcelona - Spain
Total Affiliations: 6
Document type: Journal article
Source: EUROPEAN JOURNAL OF ENDOCRINOLOGY; v. 179, n. 6, p. 391-407, DEC 2018.
Web of Science Citations: 3
Abstract

Background: Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective: To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients: A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results: Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions: Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing. (AU)

FAPESP's process: 15/25444-4 - Visit of Prof. Dr. Stephen J. Marx at the University of São Paulo collaborating with translational research projects on hereditary endocrine neoplasia
Grantee:Delmar Muniz Lourenço Jr
Support Opportunities: Research Grants - Visiting Researcher Grant - International
FAPESP's process: 13/19810-2 - Evaluation of new generation sequencing efficiency in the analysis of MEN1, CDKN2B/p15, CDKN2C/p18 CDKN1A/p21, CDKN1B/p27Kip1 and AIP genes in patients with multiple endocrine neoplasia type 1 (MEN1)
Grantee:Delmar Muniz Lourenço Jr
Support Opportunities: Regular Research Grants
FAPESP's process: 16/07504-2 - Clinical impact of the use of genetic panels based on next generation sequencing in the differential diagnosis of multiple endocrine neoplasia type 1 and analysis of potential genotype-phenotype correlations.
Grantee:Delmar Muniz Lourenço Jr
Support Opportunities: Regular Research Grants
FAPESP's process: 16/07965-0 - Clinical impact of the use of genetic panels through next generation sequencing in patients with potential risk of multiple endocrine neoplasia type 1
Grantee:Betsaida Urtremari Petenati Barros
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 13/15388-4 - Evaluation of new generation sequencing in genetic diagnosis of multiple endocrine neoplasia type 1
Grantee:Rafael Arrabaça de Carvalho
Support Opportunities: Scholarships in Brazil - Master