Whole genome sequencing of apparently mutation-negative MEN1 patients

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Fältnamn	Indikatorer	Metadata
000		03622naa a2200349 4500
001		oai:DiVA.org:uu-401244
003		SwePub
008		200107s2020 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4012442 URI
024	7	a https://doi.org/10.1530/eje-19-05222 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Backman, Samuelu Uppsala universitet,Experimentell kirurgi4 aut0 (Swepub:uu)samba267
245	1 0	a Whole genome sequencing of apparently mutation-negative MEN1 patients
264	1	b Oxford University Press (OUP),c 2020
338		a print2 rdacarrier
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Endokrinologi och diabetes0 (SwePub)302052 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Endocrinology and Diabetes0 (SwePub)302052 hsv//eng
700	1	a Bajic, Duskau Uppsala universitet,Endokrin tumörbiologi4 aut0 (Swepub:uu)dusba300
700	1	a Crona, Joakimu Uppsala universitet,Endokrin tumörbiologi,Endocrine Tumor Biology4 aut0 (Swepub:uu)joacr310
700	1	a Hellman, Peru Uppsala universitet,Endokrinkirurgi,Experimentell kirurgi4 aut0 (Swepub:uu)perhellm
700	1	a Skogseid, Brittu Uppsala universitet,Endokrin tumörbiologi4 aut0 (Swepub:uu)brittsko
700	1	a Stålberg, Peteru Uppsala universitet,Endokrinkirurgi4 aut0 (Swepub:uu)petestah
710	2	a Uppsala universitetb Experimentell kirurgi4 org
773	0	t European Journal of Endocrinologyd : Oxford University Press (OUP)g 182:1, s. 35-45q 182:1<35-45x 0804-4643x 1479-683X
856	4	u https://eje.bioscientifica.com/downloadpdf/journals/eje/182/1/EJE-19-0522.pdf
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-401244
856	4 8	u https://doi.org/10.1530/eje-19-0522

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Av författaren/redakt...: Backman, Samuel; Bajic, Duska; Crona, Joakim; Hellman, Per; Skogseid, Britt; Stålberg, Peter

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Endokrinologi oc ...

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Av lärosätet: Uppsala universitet

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