Characterization of monogenic diabetes among Sudanese children: a multi-center experience from a population with high consanguinity
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Samar S. Hassan
,
Salwa A. Musa
,
Elisa De Franco
,
Rebbeca Myers
Abstract
Objectives
Monogenic diabetes (MD) is a group of diabetes subtypes caused by defects in single genes. We report phenotypes and genotypes of MD among Sudanese children.
Methods
Referred patients (from birth to 18 years of age) with diabetes and a clinical diagnosis of MD to Gaafar Ibnauf Pediatric Tertiary Hospital or the Sudan Childhood Diabetes Center between January 2006 and April 2023 were included. Patients were divided into two groups based on onset of diabetes before six months of age (Group 1, or neonatal diabetes mellitus) or after (Group 2, or non-neonatal diabetes mellitus). Genetic testing was performed for 87 patients at the Exeter Genomics laboratory and for one patient at the University of Cambridge, Metabolic Research Laboratories, UK.
Results
Out of 88 patients, 50 were from Group 1 and 38 from Group 2. We reported consanguinity in 63.6 % of the cohort and identified disease-causing variants for 18 genes in 43.2 % (Group 1) and 37.5 % (Group 2) of patients from the total cohort. The commonest causes in Group 1 and Group 2 were pathogenic variants in the EIF2AK3 and WFS1 genes, respectively. Pathogenic variants in recently reported novel genes ZNF808, NARS2, and FICD were detected in 8.5 %, 4.2%, and 1.4 % of patients, respectively. Patients with a disrupted WFS1 gene were found to have deafness (92.8 %) and optic atrophy (64 %). While skeletal deformities and liver disease were both seen in 28.6 % of patients with pathogenic variants in the ElF2AK3 gene. Hepatomegaly and hypophosphatemic rickets were uniformly seen in patients with pathogenic variants in the SLC2A2 gene. Generalized subcutaneous tissue loss and acanthosis nigricans were main features in AGPAT2 and INSR variants, respectively.
Conclusions
Characterization of MD in Sudan showed a predominance of syndromic forms. Genetic studies conducted on consanguineous populations may raise higher probabilities in identifying rare genes.
Funding source: Diabetes UK
Award Identifier / Grant number: 19/0005994 and 21/0006335
Funding source: Wellcome Trust
Award Identifier / Grant number: Grant to Dr Robert Semple, Honorary Consultant End
Award Identifier / Grant number: Grant to Professors Andrew Hattersley and Sian Ell
Acknowledgments
The authors would like to extend their appreciation to Exeter Genomic Laboratories and University of Cambridge Institute of Metabolic Science. Special thanks to Mr. Gasmelseed Y. Ahmed, MD, PhD Biostatistician, Cardiology Department, Columbia University Medical Center, New York for statistical analysis and review.
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Research ethics: The Endocrine and Diabetes Institutional Review Board at Gaafar Ibnauf paediatric tertiary hospital, Khartoum, has approved this study under approval number GIAH/EDIRB/2023/03/0012.
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Informed consent: Written informed consent was provided from patients for genetic testing free of charge for research purpose and participation in this study with anonymized data.
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Author contributions: SH: Is the primary caring physician of some patients, conceptualized and visualized the study, collected data from records, collected blood samples from patients for genetic testing and wrote the initial drafts, and finalized the main manuscript. SM, OB, AI and GM: primary caring physicians of some patients, reviewed the manuscript and assisted in data collection. AA, JS and OA reviewed the manuscript. KP, ED, RM, RV were responsible for molecular genetic diagnostics and interpretation, reviewed the genetic sections in the manuscript, reviewed and finalized the manuscript. MA: Primary caring physician of some patients, conceptualized the study, critically reviewed and finalized the manuscript. SH, ED, MA and KP were the main generators of this work and, as such, had full access to all the data in the study and they take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors state that they have no conflicts of interests in this work. Disclosure A study on neonatal diabetes from the same centers was published in Wiley online Library, https://doi.org/10.1155/2024/2032425.
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Research funding: Genetic testing at the University of Exeter was provided free of charge (cost covered by a Wellcome Trust Senior Investigator grant to Professors Andrew Hattersley and Sian Ellard). Genetic testing at Cambridge Metabolic Institute Science for INSR mutation in one patient was provided free of charge (cost covered by Dr Robert Semple MRCP PhD, Wellcome Trust Clinician Scientist, Honorary Consultant Endocrinologist). Genetic testing was funded by Diabetes UK (19/0005994 and 21/0006335). The work is supported by the National Institute for Health Research (NIHR) Exeter Biomedical Research Centre, Exeter, UK. The funding body had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed are those of the author(s) and not necessarily those of NIHR.
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Data availability: The data of this study are not publicly available due to privacy reasons but are available from corresponding author upon request (contact Dr. Samar Hassan hassansamar2006@gmail.com).
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