ECE2023 Poster Presentations Adrenal and Cardiovascular Endocrinology (72 abstracts)
Genetic Aetiology of Primary Adrenal Insufficiency in Sudan
Chris Smith 1 , Mohamed Abdullah 2,3 , Samar Hassan 2 , Younus Qamar 1 , Charlotte Hall 1 , Saptarshi Maitra 1 , Avinaash Maharaj 1 , Lucia Mariela Marroquin Ramirez 1 , Jordan Read 1 , Li Chan 1 , Louise Metherell 1 & Salwa Musa 2,4
1WHRI, QMUL, Centre for Endocrinology, London, United Kingdom; 2Gaafar Ibn Auf Pediatric Tertiary Hospital, Department of Paediatric Endocrinology and Diabetes, Khartoum, Sudan; 3University of Khartoum, Department of Paediatrics, Khartoum, Sudan; 4Al-Neelain University, Department of Paediatrics and Child Health Faculty of Medicine, Khartoum, Sudan
Primary adrenal insufficiency (PAI) in children is usually congenital with more than 25 causal genes leading to overlapping phenotypes. A genetic diagnosis is helpful to guide management and genetic counselling but can be challenging in resource limited settings where facilities for antibodies and genetic testing may be unavailable. Studies from Africa are rare but, in Sudan, the most common genetic aetiologies for PAI are congenital adrenal hyperplasia (CAH; mostly CYP21A2) and Triple A syndrome (AAAS). Here we describe other genetic etiologies of PAI in a cohort of 29 Sudanese families. 36 patients from 29 Sudanese families (22M) were included in this series. 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; MC2R, MRAP, CYP11A1 and STAR, was followed by whole exome sequencing (WES) in mutation negative individuals and family members (where available). Qiagen Clinical Interpretation tool was used to filter variants from VCF files, and the Integrative Genomics Viewer (IGV) employed to look for small/large deletions in known causal genes. The genetic aetiology was determined in 16/29 families (n=19 patients). Only 1 individual was diagnosed by CGS, having MC2R mutation p.R146H. Other mutations were discovered in; NNT (n=5) including a novel, synonymous variant (c.2193G>A; p.T731=) causing aberrant splicing p.(Glu867_Thr731del) in three families, ABCD1 (n=4), NROB1 (n=1), CYP11A1 (n=1), and CYP11B1-CYP11B2 fusion (n=3). IGV analysis detected a deletion of the last five exons of AIRE in two families (n=4), meaning ABCD1, AIRE and NNT are the most frequently mutated genes in this population. PAI in Sudan has heterogeneous aetiology and gaining a genetic diagnosis is priceless to the patient and family, helping to guide healthcare management and provide vital information on the prognosis. Unconventional mutations in known genes or novel genes may be responsible for the remaining undiagnosed cases. CGS as a pre-screening tool may be helpful where founder effects are known, e.g. p.(T731=) mutation in NNT in Sudan, but WES and whole genome sequencing (WGS) are likely to become the standard to achieve this, with their ability to find single nucleotide variations and deletions respectively, especially where causative genes are already established. The challenge will then shift to proving the consequence of variants found, as seen here with the “silent” NNT variant.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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