Genetic aetiology of primary adrenal insufficiency in Sudan

Chris Smith; Mohamed Abdullah; Samar Hassan; Luqman Fauzi; Younus Qamar; Charlotte Hall; Saptarshi Maitra; Avinaash Maharaj; Ramirez Lucia Marroquin; Jordan Read; Li Chan; Louise Metherell; Salwa Musa

doi:10.1530/endoabs.94.P15

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Endocrine Abstracts (2023) 94 P15 | DOI: 10.1530/endoabs.94.P15

SFEBES2023 Poster Presentations Adrenal and Cardiovascular (78 abstracts)

Genetic aetiology of primary adrenal insufficiency in Sudan

Chris Smith ¹ , Mohamed Abdullah ^2,3 , Samar Hassan ² , Luqman Fauzi ¹ , Younus Qamar ¹ , Charlotte Hall ¹ , Saptarshi Maitra ¹ , Avinaash Maharaj ¹ , Lucia Marroquin Ramirez ¹ , Jordan Read ¹ , Li Chan ¹ , Louise Metherell ¹ & Salwa Musa ^2,3

Err

Author affiliations

¹Queen Mary University London, London, United Kingdom. ²Gaafar Ibn Auf paediatric Tertiary Hospital, Khartoum, Sudan. ³Al-Neelain University, Khartoum, Sudan

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. The most common genetic aetiologies for PAI in Sudan are congenital adrenal hyperplasia (CAH; mostly CYP21A2) and Triple A syndrome (AAAS). Here we investigate other genetic aetiologies of PAI in a cohort of 43 Sudanese families (n=46; 29M). Inclusion criteria were clinical presentation of PAI paired with biochemical finding of low cortisol and high ACTH, and/or a negative response to synacthen stimulation. 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), was followed by whole exome sequencing (WES), in mutation negative individuals, using QCI and IGV tools for sequence interpretation. The genetic aetiology was determined in half of the families (23/43), with only 2 mutations discovered by CGS and the rest after WES analysis. 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 others. 3 families had a splicing defect in NNT (p.T731=) and 2 families had a 5-exon deletion in AIRE, possibly representing founder mutations. PAI in Sudan has heterogeneous aetiology with a different spectrum of PAI genes than our global cohort, resulting in fewer solved cases (53% compared to 85%). CGS of founder mutations and region-specific, commonly mutated genes may be a cheaper alternative to WES for developing countries. However, WES and whole genome sequencing are likely to become the standard, with their ability to find single nucleotide variations and deletions respectively, as the cost continues to fall.