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

Arnaud Lagarde (1, 2, 3) , Grégory Mougel (1, 2, 3) , Lucie Coppin (4) , Magalie Haissaguerre (5) , Lauriane Le Collen (6) , Amira Mohamed (7) , Marc Klein (8) , Marie-Françoise Odou , Antoine Tabarin (5) , Hedia Brixi (9) , Thomas Cuny (1, 2, 10) , Brigitte Delemer , Anne A. Barlier (1, 2, 3) , Pauline Romanet (1, 2, 3)

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 MarMaRa - Institut Marseille Maladies Rares
3 Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM]
4 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
5 Hôpital cardiologique du Haut Leveque
6 Laboratoire de Microbiologie
7 LA CONCEPTION - Hôpital de la Conception [CHU - APHM]
8 Hôpital Brabois
9 CHU Reims - Centre Hospitalier Universitaire de Reims
10 Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM]

Purpose Mosaicism is a feature of several inherited tumor syndromes. Only a few cases of mosaicism have been described in multiple endocrine neoplasia type 1 (MEN1). 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 two lesions. Conclusion We report here three 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.

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology; Life Sciences [q-bio]; Genetics; Life Sciences [q-bio]; Human health and pathology; Endocrinology and metabolism

Arnaud Lagarde, Grégory Mougel, Lucie Coppin, Magalie Haissaguerre, Lauriane Le Collen, et al.. Systematic detection of mosaicism by using digital NGS reveals three new MEN1 mosaicisms. Endocrine Connections, 2022, 11 (11), ⟨10.1530/EC-22-0093⟩. ⟨hal-04013616⟩