8482 Genetic Aetiology Of Primary Adrenal Insufficiency In Sudan

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Abstract Disclosure: C.J. Smith: None. M.A. Abdullah: None. S.S. Hassan: None. L.S. Fauzi: None. Y. Qamar: None. C.L. Hall: None. S. Maitra: None. A.V. Maharaj: None. L.M. Marroquin Ramirez: None. J.E. Read: None. L. Chan: None. L. Metherell: None. S.A. Musa: None. Primary adrenal insufficiency (PAI) in children is usually congenital with more than 25 causal genes with overlapping phenotypes. Genetic diagnosis helps to guide management and genetic counselling but can be challenging in resource limited settings. PAI is understudied in African children but in a cohort of Sudanese individuals (n>400) the majority had congenital adrenal hyperplasia (>73% CAH; mostly due to CYP21A2 mutation), with Triple A syndrome (AAAS), auto-immune polyendocrinopathy syndrome or adrenoleukodystrophy accounting for a further 11%. Here, we describe genetic characterization of the remainder of the cohort. 46 patients from 41 families (29 male and 17 female) with clinical presentation of PAI paired with biochemical finding of (low cortisol ± high ACTH and/or a negative response to Synacthen stimulation) were included in this study. Exclusion criteria were clinical and/or genetic diagnosis of CAH or Triple A syndrome. Candidate gene sequencing (CGS) of commonly causative genes in our global cohort (mostly European ancestry), MC2R, MRAP, CYP11A1 and STAR, was followed by whole exome sequencing (WES), in mutation negative individuals and family members. WES results and segregation within families were confirmed by Sanger sequencing. In silico tools were utilised for predicting the result of possible splicing mutations and these were functionally assessed using the Exon Trap vector (MoBi tech). The genetic aetiology was determined in over half of the families (23/41). Mutations in ABCD1 (7/23), NNT (5/23), AIRE (3/23) and CYP11A1 (3/23) were most common in this population with mutations in HSD3B2, MC2R, NR0B1, STAR and a CYP11B1-B2 fusion event accounting for the remaining genetically diagnosed families. 3 families had a splicing defect in NNT (c.9193G>A) and 2 families had a 5-exon deletion in AIRE, possibly representing founder mutations. PAI in Sudan has a heterogeneous aetiology with a different spectrum of PAI genes than our global cohort, resulting in fewer solved cases (53% compared to 85%) with only two families containing variants in common (European) candidate genes. While WES was pivotal in the study, in resource limited settings sequencing of founder mutations and region-specific, commonly mutated genes may be a cheaper alternative and both increase and hasten the diagnosis rate of at-risk patients. Whether the remaining cases without a diagnosis have unconventional defects in known genes, mutations in novel gene(s), and/or new syndromes incorporating permanent or transitory AI remains to be investigated. Presentation: 6/2/2024

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