PMID- 31658439
OWN - NLM
STAT- MEDLINE
DCOM- 20200316
LR  - 20220412
IS  - 1479-683X (Electronic)
IS  - 0804-4643 (Linking)
VI  - 182
IP  - 1
DP  - 2020 Jan
TI  - Whole genome sequencing of apparently mutation-negative MEN1 patients.
PG  - 35-45
LID - EJE-19-0522 [pii]
LID - 10.1530/EJE-19-0522 [doi]
AB  - OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant 
      syndrome usually caused by loss-of-function mutations in the MEN1 gene. However, 
      a minority of patients who fulfill the criteria for MEN1 are not found to harbor 
      MEN1 mutations. Besides, some of these individuals, present with a subtly 
      different phenotype suggestive of sporadic disease. The aim of the present study 
      was to investigate the genetic architecture of mutation-negative MEN1. DESIGN: 
      Fourteen patients with a clinical diagnosis (n = 13) or suspicion (n = 1) of MEN1 
      who had negative genetic screening of the MEN1 gene were included. METHODS: 
      Constitutional DNA from the included patients, as well as tumor DNA from six of 
      the patients, was subjected to whole genome sequencing. Constitutional variants 
      were filtered against population databases and somatic variants were studied 
      under a tumor-suppressor model. RESULTS: Three patients carried pathogenic 
      variants (two splice-site variants, one missense variant) in MEN1 that had not 
      been detected during routine clinical sequencing, one patient carried a 
      pathogenic variant in CASR and one patient carried a gross deletion on chromosome 
      1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients 
      without mutations did not detect any recurrent genes fulfilling Knudson's two-hit 
      model. CONCLUSION: These results highlight the possibility of germline mutations 
      being missed in routine screening, the importance of considering phenocopies in 
      atypical or mutation-negative cases. The absence of apparent disease-causing 
      mutations suggests that a fraction of MEN1 mutation-negative MEN1 cases may be 
      due to the chance occurrence of several endocrine tumors in one patient.
FAU - Backman, Samuel
AU  - Backman S
AD  - Departments of Surgical Sciences, Uppsala University, Uppsala, Sweden.
FAU - Bajic, Duska
AU  - Bajic D
AD  - Departments of Medical Sciences, Uppsala University, Uppsala, Sweden.
FAU - Crona, Joakim
AU  - Crona J
AD  - Departments of Medical Sciences, Uppsala University, Uppsala, Sweden.
FAU - Hellman, Per
AU  - Hellman P
AD  - Departments of Surgical Sciences, Uppsala University, Uppsala, Sweden.
FAU - Skogseid, Britt
AU  - Skogseid B
AD  - Departments of Medical Sciences, Uppsala University, Uppsala, Sweden.
FAU - Stalberg, Peter
AU  - Stalberg P
AD  - Departments of Surgical Sciences, Uppsala University, Uppsala, Sweden.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Eur J Endocrinol
JT  - European journal of endocrinology
JID - 9423848
RN  - 0 (CDC73 protein, human)
RN  - 0 (Tumor Suppressor Proteins)
SB  - IM
MH  - Female
MH  - Genetic Testing
MH  - Germ-Line Mutation/genetics
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Multiple Endocrine Neoplasia Type 1/*genetics
MH  - Mutation/*genetics
MH  - Phenotype
MH  - Tumor Suppressor Proteins/genetics
MH  - Whole Genome Sequencing/*methods
EDAT- 2019/10/29 06:00
MHDA- 2020/03/17 06:00
CRDT- 2019/10/29 06:00
PHST- 2019/07/08 00:00 [received]
PHST- 2019/10/28 00:00 [accepted]
PHST- 2019/10/29 06:00 [pubmed]
PHST- 2020/03/17 06:00 [medline]
PHST- 2019/10/29 06:00 [entrez]
AID - EJE-19-0522 [pii]
AID - 10.1530/EJE-19-0522 [doi]
PST - ppublish
SO  - Eur J Endocrinol. 2020 Jan;182(1):35-45. doi: 10.1530/EJE-19-0522.