ECE2019 Oral Communications Adrenal 2 (5 abstracts)
Genetic predisposition to Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH): next generation sequencing ARMC5, NR3C1 (glucocorticoid receptor) and PDE11A4 (phosphodiesterase 11) in 389 patients
Anna Vaczlavik 1 , Patricia Vaduva 1 , Lucas Bouys 1 , Mario Néou 1 , Amandine Septier 1 , Victor Heurtier 1 , Rossella Libé 2 , Matthias Kroiss 3 , Françoise Borson-Chazot 4 , Philippe Chanson 5 , Marie-Christine Vanthyghem 6 , Antoine Tabarin 7 , Guillaume Assié 1 , Constantine Stratakis 8 , Maria Fragoso 9 , Bruno Ragazzon 1 & Jérôme Bertherat 1
1Cochin Institute, Paris, France; 2University Hospital Cochin, Paris, France; 3University Hospital Würzburg, Würzburg, Germany; 4University Hospital Lyon, Lyon, France; 5University Paris-Sud, Paris, France; 6University Hospital Lille, Lille, France; 7University Hospital Bordeaux, Bordeaux, France; 8NIH, Bethesda, USA; 9Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo & ICESP, São Paulo, Brazil.
Introduction: PBMAH is an heterogeneous disease from the clinical, hormonal, and morphological point of view. ARMC5 inactivating mutations have been reported as a cause of PBMAH. PDE11A4 variants have been associated with PBMAH and NR3C1 variants with bilateral adrenal incidentalomas.
Aim: To analyse the frequency of ARMC5 pathogenic mutations and PDE11A4 and NR3C1 variants in PBMAH patients.
Methods: ARMC5, PDE11A4 and NR3C1 were sequenced on leucocyte DNA by NGS using Ion Torrent technology in 389 PBMAH index cases. Identified variants were then annotated using Annovar tool. Combined bioinformatic filters (sequence depth more than 5, allelic ratio more than 0,1 and total population frequency according to Exac less than 5%) and visual validation using Integrative Genomics Viewer (IGV) software were used in order to identify and retain the variants.
Results: Pathogenic ARMC5 mutations are present in 75 patients (20%). PDE11A4 and NR3C1variants were observed respectively in 23.4% and 8.9% of the patients. The overall frequency of PDE11A4 variants was similar in ARMC5 mutated and wild type (WT) patients (P:0.88), while NR3C1 variants were more frequent in the ARMC5 WT (P:0.04). The following PDE11A missense variants already known for altering enzymatic activity have been found: p.R804H in 15 patients (13 ARMC5 WT), p.R867G in 14 patients (9 ARMC5 WT), p.M878V (9 ARMC5 WT) and p.D609N (in 1 ARMC5 mutated patient). Interestingly a stop codon mutation initially reported in Micronodular Adrenal Hyperplasia (p.R307X) was identified in 1 ARMC5 mutated and in 3 ARMC5 WT. Five NR3C1 variants have been found: 3 already known as polymorphism: p.R23K, p.F65V, p.N363S. The last one is associated with high glucocorticoid sensitivity and bilateral adrenal incidentalomas (1 in the ARMC5 mutated, 18 in ARMC5 WT) whereas the first one is associated with healthier metabolic profile (1 in ARMC5 MUT, 9 in ARMC5 WT). Two variants not previously reported have been identified: p.S404P predicted benign in 1 patient; p. N454S predicted pathogenic in 1 patient.
Conclusion: These results show that clear pathogenic mutations of PDE11A4 and NR3C1 are probably rare in PBMAH. By contrast variants that might change the activity of the phosphosphodiesterase or the sensitivity to glucocorticoids are present in PBMAH patients regardless of the ARMC5 status. Genotype/phenotype correlation analysis will help to determine their potential role in the modulation of the disease phenotype, both in term of PBMAH development or complications of cortisol excess.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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