Polygenic risk score for autoimmune Addison

Maribel Aranda-Guillen; Ileana R. Botusan; Venuja Fernando; Ellen Royrvik; Boe Wolff Anette Susanne; Stefan Johansson; Husebye Eystein Sverre; Sophie Bensing; Olle Kampe; Daniel Eriksson

doi:10.1530/endoabs.99.EP736

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Endocrine Abstracts (2024) 99 EP736 | DOI: 10.1530/endoabs.99.EP736

ECE2024 Eposter Presentations Adrenal and Cardiovascular Endocrinology (155 abstracts)

Polygenic risk score for autoimmune Addison’s disease combined with whole-genome sequencing identifies patients with undiagnosed monogenic primary adrenal insufficiency

Maribel Aranda-Guillen ¹ , Ileana R. Botusan ^1,2 , Venuja Fernando ¹ , Ellen Røyrvik ^3,4,5 , Anette Susanne Bøe Wolff ^3,4,6 , Stefan Johansson ^3,7 , Eystein Sverre Husebye ^1,3,4,6 , Sophie Bensing ^2,8 , Olle Kämpe ^1,2 & Daniel Eriksson ^1,9

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Author affiliations

¹Karolinska Institutet, Center for Molecular Medicine, Department of Medicine, Solna, Stockholm, Sweden; ²Karolinska University Hospital, Department of Endocrinology, Stockholm, Sweden; ³University of Bergen, Department of Clinical Science, Bergen, Norway; ⁴K.G. Jebsen Center for Autoimmune Disorders, Bergen, Norway; ⁵Norwegian Institute of Public Health, Department of Genetics and Bioinformatics, Bergen, Norway; ⁶Haukeland University Hospital, Department of Medicine, Bergen, Norway; ⁷Haukeland University Hospital, Department of Medical Genetics, Bergen, Norway; ⁸Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; ⁹Uppsala University, Department of Immunology, Genetics and Pathology, Uppsala, Sweden

Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison’s disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14_AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD.

Methods: We calculated the PRS14_AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35).

Results: Among the 35 patients, monogenic PAI was found in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 rediagnosed patients developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants.

Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling