SFEIES24 Poster Presentations Adrenal & Cardiovascular (40 abstracts)
WES as a tool for differential diagnosis of adrenal insufficiency in sudanese children
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 , Salwa Musa 2,4 & Louise Metherell 1
1WHRI, QMUL, London, United Kingdom; 2Gaafar Ibn Auf Paediatric Tertiary Hospital, Khartoum, Sudan; 3University of Khartoum, Khartoum, Sudan; 4Al-Neelain University, Khartoum, Sudan
Studies of adrenal insufficiency (AI) in African children are rare and diagnosis is challenging, especially in resource limited settings where biochemical and genetic testing are restricted. We describe the genetic characterisation of a cohort of Sudanese children, identifying founder effects and commonly mutated genes that will improve their treatment, expand our knowledge of AI, and expedite diagnosis of future patients. 48 patients from 43 families (31M:17F) with presentation of AI paired with biochemical finding of low cortisol ± high ACTH were included in this study. Exclusion criteria were clinical and/or genetic diagnosis of CAH or Triple A syndrome. Additional co-morbidities observed in some patients included white matter changes, muscular dystrophy, gait abnormalities, cataracts, obesity, and deafness. Whole exome sequencing (WES), copy number variation analysis (CNV), variant prioritisation (Exomiser/QCI) and splice predictions (SQUIRLS) were performed as a genetic diagnostic pipeline. Variants were confirmed by Sanger sequencing and possible splicing mutations were functionally assessed using the Exon Trap vector (MoBi-tech). Genetic diagnosis was achieved for 26/43 families, with mutations in ABCD1 (7), NNT (5), AIRE (3) the most affected genes. CNV analysis identified a CYP11B1-2 fusion event and a deletion incorporating 5-exons of AIRE, and 2 downstream genes. This AIRE deletion was identified in 2 unrelated families and 3 patients from 2 families had a splicing defect in NNT (c.9193G>A) which resulted in partial exon skipping. Incidental findings in MC4R, ADGRV1, and CNDP1 are likely to be causative of the obesity, cataracts and deafness, and abnormal gait respectively observed in patients. This study has not only diagnosed 60% of our Sudanese cohort but also identified commonly mutated genes and 2 possible founder effects. Sanger sequencing of bespoke candidate genes might provide a cheaper alternative, increase, and hasten the diagnosis rate of at-risk patients in resource limited settings.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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