PMID- 30324798
OWN - NLM
STAT- MEDLINE
DCOM- 20181211
LR  - 20181211
IS  - 1479-683X (Electronic)
IS  - 0804-4643 (Linking)
VI  - 179
IP  - 6
DP  - 2018 Dec 1
TI  - Germline mutation landscape of multiple endocrine neoplasia type 1 using full 
      gene next-generation sequencing.
PG  - 391-407
LID - EJE-18-0430 [pii]
LID - 10.1530/EJE-18-0430 [doi]
AB  - 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.
FAU - Carvalho, Rafael A
AU  - Carvalho RA
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
FAU - Urtremari, Betsaida
AU  - Urtremari B
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
FAU - Jorge, Alexander A L
AU  - Jorge AAL
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
FAU - Santana, Lucas S
AU  - Santana LS
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
FAU - Quedas, Elisangela P S
AU  - Quedas EPS
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
FAU - Sekiya, Tomoko
AU  - Sekiya T
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
FAU - Longuini, Viviane C
AU  - Longuini VC
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
FAU - Montenegro, Fabio L M
AU  - Montenegro FLM
AD  - Unidade de Paratireoide, Laboratorio de Cirurgia Vascular e da Cabeca e Pescoco 
      LIM-28, Disciplina de Cirurgia de Cabeca e Pescoco, Hospital das Clinicas 
      HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, 
      Brazil.
FAU - Lerario, Antonio M
AU  - Lerario AM
AD  - Division of Metabolism, Department of Internal Medicine, Endocrinology and 
      Diabetes, University of Michigan, Ann Arbor, Michigan, USA.
FAU - Toledo, Sergio P A
AU  - Toledo SPA
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
AD  - Endocrinology Division, Federal University of Sao Paulo (UNIFESP), Sao Paulo, 
      Brazil.
FAU - Marx, Stephen J
AU  - Marx SJ
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
AD  - Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and 
      Human Development (NICHD), Bethesda, Maryland, USA.
FAU - Toledo, Rodrigo A
AU  - Toledo RA
AD  - Vall d'Hebron Institute of Oncology, Barcelona, Spain.
FAU - Lourenco, Delmar M Jr
AU  - Lourenco DM Jr
AD  - Unidade de Endocrinologia Genetica UEG, Laboratorio de Endocrinologia Celular e 
      Molecular LIM-25, Disciplina de Endocrinologia.
AD  - Disciplina de Endocrinologia, Instituto do Cancer do Estado de Sao Paulo ICESP, 
      Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Eur J Endocrinol
JT  - European journal of endocrinology
JID - 9423848
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Female
MH  - Genetic Variation/genetics
MH  - Germ-Line Mutation/*genetics
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Multiple Endocrine Neoplasia/*diagnosis/*genetics
MH  - Proto-Oncogene Proteins/*genetics
MH  - Sequence Analysis, DNA/*methods
MH  - Young Adult
EDAT- 2018/10/17 06:00
MHDA- 2018/12/12 06:00
CRDT- 2018/10/17 06:00
PHST- 2018/05/19 00:00 [received]
PHST- 2018/09/24 00:00 [accepted]
PHST- 2018/10/17 06:00 [pubmed]
PHST- 2018/12/12 06:00 [medline]
PHST- 2018/10/17 06:00 [entrez]
AID - EJE-18-0430 [pii]
AID - 10.1530/EJE-18-0430 [doi]
PST - ppublish
SO  - Eur J Endocrinol. 2018 Dec 1;179(6):391-407. doi: 10.1530/EJE-18-0430.