PMID- 34897474 OWN - NLM STAT- MEDLINE DCOM- 20220415 LR - 20220415 IS - 1945-7197 (Electronic) IS - 0021-972X (Linking) VI - 107 IP - 4 DP - 2022 Mar 24 TI - Noninvasive Prenatal Diagnosis of a Paternally Inherited MEN1 Pathogenic Splicing Variant. PG - e1367-e1373 LID - 10.1210/clinem/dgab894 [doi] AB - CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1. The uncertainty of pathogenicity of MEN1 variants complexifies the selection of the patients likely to benefit from specific care. OBJECTIVE: MEN1-mutated patients should be offered tailored tumor screening and genetic counseling. We present a patient with hyperparathyroidism for whom genetic analysis identified a variant of uncertain significance in the MEN1 gene (NM_130799.2): c.654G > T p.(Arg218=). Additional functional genetic tests were performed to classify the variant as pathogenic and allowed prenatal testing. DESIGN: Targeted next generation sequencing identified a synonymous variant in the MEN1 gene in a 26-year-old male with symptomatic primary hyperparathyroidism. In silico and in vitro genetic tests were performed to assess variant pathogenicity. RESULTS: Genetic testing of the proband's unaffected parents showed the variant occurred de novo. Transcript study showed a splicing defect leading to an in-frame deletion. The classification of the MEN1 variant as pathogenic confirmed the diagnosis of MEN1 and recommended an adapted medical care and follow-up. Pathogenic classification also allowed to propose a genetic counseling to the proband and his wife. Noninvasive prenatal diagnosis was performed with a personalized medicine-based protocol by detection of the paternally inherited variant in maternal plasmatic cell free DNA, using digital PCR. CONCLUSION: We showed that functional genetic analysis can help to assess the pathogenicity of a MEN1 variant with crucial consequences for medical care and genetic counseling decisions. CI - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Huby, Thomas AU - Huby T AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. FAU - Le Guillou, Edouard AU - Le Guillou E AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. FAU - Burin des Roziers, Cyril AU - Burin des Roziers C AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. AD - Institut Cochin, Inserm U1016, CNRS UMR8104, Universite de Paris, CARPEM, Paris, France. FAU - Pacot, Laurence AU - Pacot L AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. AD - Institut Cochin, Inserm U1016, CNRS UMR8104, Universite de Paris, CARPEM, Paris, France. FAU - Briand-Suleau, Audrey AU - Briand-Suleau A AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. AD - Institut Cochin, Inserm U1016, CNRS UMR8104, Universite de Paris, CARPEM, Paris, France. FAU - Chansavang, Albain AU - Chansavang A AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. AD - Institut Cochin, Inserm U1016, CNRS UMR8104, Universite de Paris, CARPEM, Paris, France. FAU - Toussaint, Aurelie AU - Toussaint A AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. FAU - Duchossoy, Veronique AU - Duchossoy V AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. FAU - Vaucouleur, Nicolas AU - Vaucouleur N AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. FAU - Benoit, Virginie AU - Benoit V AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. FAU - Lode, Laurence AU - Lode L AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. FAU - Molac, Clemence AU - Molac C AD - Maternite Port-Royal, FHU PREMA, AP-HP, Hopital Cochin, AP-HP.Centre-Universite de Paris, Universite de Paris, Paris, France. FAU - North, Marie-Odile AU - North MO AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. FAU - Grotto, Sarah AU - Grotto S AD - Maternite Port-Royal, FHU PREMA, AP-HP, Hopital Cochin, AP-HP.Centre-Universite de Paris, Universite de Paris, Paris, France. FAU - Tsatsaris, Vassilis AU - Tsatsaris V AUID- ORCID: 0000-0002-7650-6660 AD - Maternite Port-Royal, FHU PREMA, AP-HP, Hopital Cochin, AP-HP.Centre-Universite de Paris, Universite de Paris, Paris, France. FAU - Jouinot, Anne AU - Jouinot A AD - Department of Endocrinology, Hopital Cochin, AP-HP.Centre-Universite de Paris, Universite de Paris, Paris, France. FAU - Cochand-Priollet, Beatrix AU - Cochand-Priollet B AD - Department of Pathology, Cochin Hospital, AP-HP.Centre-Universite de Paris, Universite de Paris, Paris, France. FAU - Paepegaey, Anne-Cecile AU - Paepegaey AC AD - Department of Endocrinology, Medipole Hopital Mutualiste, Villeurbanne, France. FAU - Nectoux, Juliette AU - Nectoux J AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. FAU - Groussin, Lionel AU - Groussin L AD - Department of Endocrinology, Hopital Cochin, AP-HP.Centre-Universite de Paris, Universite de Paris, Paris, France. FAU - Pasmant, Eric AU - Pasmant E AUID- ORCID: 0000-0002-1881-8762 AD - Service de Genetique et Biologie Moleculaires, Hopital Cochin, DMU BioPhyGen, Assistance Publique-Hopitaux de Paris, AP-HP.Centre-Universite de Paris, Paris, France. AD - Institut Cochin, Inserm U1016, CNRS UMR8104, Universite de Paris, CARPEM, Paris, France. LA - eng PT - Case Reports PT - Journal Article PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 SB - IM MH - Adult MH - Female MH - Genetic Testing MH - Humans MH - *Hyperparathyroidism/genetics MH - Male MH - *Multiple Endocrine Neoplasia Type 1/genetics MH - *Noninvasive Prenatal Testing MH - Paternal Inheritance MH - Pregnancy OTO - NOTNLM OT - MEN1 OT - genetic counseling OT - hyperparathyroidism OT - interpretation of genetic variant OT - noninvasive prenatal test EDAT- 2021/12/14 06:00 MHDA- 2022/04/16 06:00 CRDT- 2021/12/13 13:27 PHST- 2021/08/11 00:00 [received] PHST- 2021/12/14 06:00 [pubmed] PHST- 2022/04/16 06:00 [medline] PHST- 2021/12/13 13:27 [entrez] AID - 6460432 [pii] AID - 10.1210/clinem/dgab894 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1367-e1373. doi: 10.1210/clinem/dgab894.