Diagnosis of mosaic mutations in the MEN1 gene by next generation sequencing

Coppin, Lucie; Ferrière, Amandine; Crépin, Michel; Haissaguerre, Magalie; Ladsous, M.; Tabarin, Antoine; Odou, Marie-Françoise

doi:10.1530/eje-18-0852

Cited by 12 publications

(17 citation statements)

References 6 publications

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“…The MEN1 gene is located on chromosome 11q13.1 and encodes a ubiquitously expressed transcription cofactor of cyclins; MEN1 also participates in G1/S checkpoint regulation (8,9). Approximately 10% of all MEN1related PA cases can be attributed to de novo mutations, which are sometimes identified as a mosaicism in the proband (10,11).…”

Section: Multiple Endocrine Neoplasia Type 1 Syndromementioning

confidence: 99%

Genetic and Epigenetic Causes of Pituitary Adenomas

et al. 2021

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Pituitary adenomas (PAs) can be classified as non-secreting adenomas, somatotroph adenomas, corticotroph adenomas, lactotroph adenomas, and thyrotroph adenomas. Substantial advances have been made in our knowledge of the pathobiology of PAs. To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and X-LAG syndromes. PAs have also been described in association with succinate dehydrogenase-related familial PA, neurofibromatosis type 1, and von Hippel–Lindau, DICER1, and Lynch syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the deubiquitinase gene USP8, USP48, and BRAF mutations are associated with adrenocorticotropic hormone production. In this review, we describe the genetic and epigenetic landscape of PAs and summarize novel insights into the regulation of pituitary tumorigenesis.

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Section: Multiple Endocrine Neoplasia Type 1 Syndromementioning

confidence: 99%

Genetic and Epigenetic Causes of Pituitary Adenomas

et al. 2021

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“…UMIs (see also supplemental data) Firstly, we analyzed the DNA from a patient who presented with a known mosaic MEN1 pathogenic variant, quantified at an AF of 5.1% using ultra-deep NGS (patient A, Supplemental Table 1) (14).…”

Section: Validation and Analytical Performance Of Mosaicism Detection...mentioning

confidence: 99%

“…Next generation sequencing (NGS) offers new possibilities for detecting mosaic variants (7,8,14,16,17,18). Here we set up targeted NGS using unique molecular identifiers (UMI, the UMI principle described in supplemental data) to systematically search for MEN1 mosaicism using blood DNA in unresolved MEN1 index cases showing at least two lesions, and determined the performance of such analysis in a cohort of 119 patients.…”

Section: Introductionmentioning

confidence: 99%

Systematic detection of mosaicism by using digital NGS reveals three new MEN1 mosaicisms

Lagarde

Mougel

Coppins

et al. 2022

Endocrine Connections

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Purpose: Mosaicism is a feature of several inherited tumor syndromes. Only few cases of mosaicism in Multiple Endocrine Neoplasia type 1 (MEN1) have been described. Next generation sequencing (NGS) offers new possibilities for detecting mosaicism. Here we report the first study to systematically look for MEN1 mosaicism, using blood DNA, in MEN1-suspected patients but without MEN1 pathogenic variants (PV) in a heterozygous state. Methods: digital targeted NGS, including unique molecular identifiers (UMIs), was performed in routine practice and the analytic performance of this method was verified. Results: Among a cohort of 119 patients harboring from 2 to 5 MEN1 lesions, we identified 3 patients with MEN1 mosaic PVs. The allele frequencies ranged from 2.3 to 9.5%. The detection rate of MEN1 mosaicism in patients bearing at least 3 MEN1 lesions was 17% (3/18). No cases were detected in patients with 2 lesions. Conclusion: We report here 3 new cases with MEN1 mosaicism. This study examined the performance of UMI in the diagnosis of MEN1 mosaicism in routine practice and our results underline that the frequency of mosaicism is probably underestimated in patients with suspected MEN1.

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“…Although the family history should provide insight into the mode of inheritance, occasionally diagnostic confusion may arise. For example, both germline and somatic mosaicism have been reported in the setting of MEN1 3,30 …”

Section: Identification Of Monogenic Disorders Of Calcium Homeostasis...mentioning

confidence: 99%

“…Thus, if the result is incongruent with the patient's phenotype, further clinical and/or genetic assessment may be required 1 . For example, a change in genetic testing platform may yield the diagnosis as illustrated by the identification of MEN1 mutations using next generation sequencing in patients in whom previous MEN1 sequencing had not identified a causative mutation 30,36 . Finally, following the identification of a pathogenic/likely pathogenic variant, predictive testing of family members is warranted with the provision of relevant genetic counselling.…”

Section: Genetic Testing Workflowmentioning

confidence: 99%

Genetics of monogenic disorders of calcium and bone metabolism

Newey

Hannan

Wilson

et al. 2021

Clinical Endocrinology

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Disorders of calcium homeostasis are the most frequent metabolic bone and mineral disease encountered by endocrinologists. These disorders usually manifest as primary hyperparathyroidism (PHPT) or hypoparathyroidism (HP), which have a monogenic aetiology in 5%–10% of cases, and may occur as an isolated endocrinopathy, or as part of a complex syndrome. The recognition and diagnosis of these disorders is important to facilitate the most appropriate management of the patient, with regard to both the calcium‐related phenotype and any associated clinical features, and also to allow the identification of other family members who may be at risk of disease. Genetic testing forms an important tool in the investigation of PHPT and HP patients and is usually reserved for those deemed to be an increased risk of a monogenic disorder. However, identifying those suitable for testing requires a thorough clinical evaluation of the patient, as well as an understanding of the diversity of relevant phenotypes and their genetic basis. This review aims to provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders, primarily focusing on those associated with abnormal calcium homeostasis, and aims to provide a practical guide to the implementation of genetic testing in the clinic.

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Diagnosis of mosaic mutations in the MEN1 gene by next generation sequencing

Cited by 12 publications

References 6 publications

Genetic and Epigenetic Causes of Pituitary Adenomas

Genetic and Epigenetic Causes of Pituitary Adenomas

Systematic detection of mosaicism by using digital NGS reveals three new MEN1 mosaicisms

Genetics of monogenic disorders of calcium and bone metabolism

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