ECEESPE2025 Poster Presentations Adrenal and Cardiovascular Endocrinology (169 abstracts)
The genetics of adrenal insufficiency, evolution of methodologies over 35 years in a single centre
Chris Smith 1 , Rathi Prasad 1 , Claire Hughes 1 , Avinaash Maharaj 1 , Younus Qamar 1 , Saptarshi Maitra 1 , Claire Hutchison 1 , Lucia Marroquin Ramirez 1 , Luqman Fauzi 1 , Jordan Read 1 , Charlotte Hall 1 , Marwa Mohammedali 1 , Ashwini Maudhoo 1 , Helen Storr 1 , Adrian Clark 1 , Li Chan 1 & Louise Metherell 1
1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
JOINT3492
Background: Primary adrenal insufficiency (PAI) is life-threatening and can present alone or in combination with other co-morbidities. Paediatric primary adrenal insufficiency (PPAI) is most commonly congenital adrenal hyperplasia (CAH) caused by mutations in CYP21A2, but there are >25 other genetic aetiologies.
Methods: We investigated 369 families (probands 43% female, 57% male) from 36 countries with non-CAH PAI between 1990 and 2025 using candidate gene and next generation sequencing (NGS) techniques including targeted panel [TPS], whole exome [WES] and whole genome sequencing [WGS]. Challenges in coverage between different capture/sequencing methodologies were minimised by repeat sequencing and recent reanalysis of NGS data using the Genome Analysis Toolkit (GATK) and Exomiser as well as CNV assessment building towards a novel in house pipeline for diagnosis. Further analyses to assess pathogenicity included in silico e.g. SQUIRLS and functional analyses involved splice assays and heterologous expression of mutants vs wild-types.
Results: Although mean age of presentation was 3y it ranged from neonatal to 81y with a median age of 1.5y. Eight novel genetic causes of PAI were discovered with genes responsible for isolated glucocorticoid deficiency (MC2R, MRAP), with/without additional mineralocorticoid deficiency (NNT, TXNRD2) or as part of a syndrome (MCM4, SGPL1, PPOX, CPOX). Overall, a genetic diagnosis was achieved in 245/369(66.3%) families, 109 were diagnosed by CGS, 35 by TPS and 101 by WES, with WGS useful as an adjunct to define the co-ordinates of deletion mutations but adding no new diagnoses. Pathogenic variants occurred in 17 genes: MC2R (20%), MRAP (15.9%), NNT (14.2%), CYP11A1 (9.8%), STAR (9%), ABCD1 (7.4%), AAAS (5.3%), NR0B1 (DAX-1; 2.9%), TXNRD2, SGPL1, AIRE CYP11B1, CYP11A2, HSD3B2, POMC, POR and PPOX. MC2R/MRAP were most prevalent, responsible for 23.9% of cases, with the UK variant of MC2R (S74I) very common (49% of MC2R diagnoses) and for MRAP the majority of mutations were at the splice junction of exon1/intron 1. We have evolved a novel pipeline whereby sequencing of small frequently mutated genes/exons is followed by NGS where these prove negative.
Conclusion: PPAI is most commonly congenital, and, with our serial sequencing and analysis pipeline, a genetic diagnosis is achievable for >65% of cases in a cost-effective and timely manner. Distinguishing between isolated and syndromic adrenal insufficiency means treatment, ongoing management and genetic counselling can be personalised.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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