Genetic diagnosis in Sudanese and Tunisian families with syndromic intellectual disability through exome sequencing.
Annals of Human Genetics. 2022-02-03; :
DOI: 10.1111/ahg.12460
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Yahia A(1)(2)(3)(4), Ayed IB(5)(6), Hamed AA(7), Mohammed IN(7), Elseed MA(7), Bakhiet AM(8), Guillot-Noel L(3)(4), Abozar F(9), Adil R(9), Emad S(9), Abubaker R(10)(11), Musallam MA(9), Eltazi IZM(9), Omer Z(12), Maaroof OM(13), Soussi A(5), Bouzid A(5), Kmiha S(14)(15), Kamoun H(6)(14), Salih MA(16)(17), Ahmed AE(18), Elsayed L(1)(19), Masmoudi S(5), Stevanin G(3)(4).
Author information:
(1)Department of Biochemistry, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
(2)Department of Biochemistry, Faculty of Medicine, National University, Khartoum, Sudan.
(3)Institut du Cerveau – Paris Brain Institute, ICM, Sorbonne Université, INSERM,
CNRS, APHP, Paris, France.
(4)Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France.
(5)Laboratory of Molecular and Cellular Screening Processes (LPCMC), LR15CBS07, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia.
(6)Medical Genetic Department, Hedi Chaker Hospital, Sfax, Tunisia.
(7)Department of Pediatrics, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
(8)Department of Psychiatry, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
(9)Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
(10)Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
(11)National University Biomedical Research Institute (NUBRI), National University, Khartoum, Sudan.
(12)Department of Hematology and Medical Oncology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
(13)Council of Diagnostic Radiology, Sudan Medical Specialization Board, Khartoum, Sudan.
(14)Laboratory of Human Molecular Genetics, LR33ES99, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia.
(15)Department of pediatrics, Hedi Chaker Hospital, Sfax, Tunisia.
(16)Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
(17)Department of Pediatrics, College of Medicine, AlMughtaribeen University, Khartoum, Sudan.
(18)Department of Physiology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
(19)Department of Basic Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, 11671, Saudi Arabia.
BACKGROUND: Intellectual disability is a form of neurodevelopmental disorders that begin in childhood and is characterized by substantial intellectual difficulties as well as difficulties in conceptual, social, and practical areas of living. Several genetic and nongenetic factors contribute to its development; however, its most severe forms are generally attributed to single-gene defects. High-throughput technologies and data sharing contributed to the diagnosis of hundreds of single-gene intellectual disability subtypes.
METHOD: We applied exome sequencing to identify potential variants causing syndromic intellectual disability in six Sudanese patients from four unrelated families. Data sharing through the Varsome portal corroborated the diagnosis of one of these patients and a Tunisian patient investigated through exome sequencing. Sanger sequencing validated the identified variants and their segregation with the phenotypes in the five studied families.
RESULT: We identified three pathogenic/likely pathogenic variants in CCDC82, ADAT3, and HUWE1 and variants of uncertain significance in HERC2 and ATP2B3. The patients with the CCDC82 variants had microcephaly and spasticity, two signs absent in the two previously reported families with CCDC82-related intellectual disability.
CONCLUSION: In conclusion, we report new patients with pathogenic mutations in the genes CCDC82, ADAT3, and HUWE1. We also highlight the possibility of extending the CCDC82-linked phenotype to include spastic paraplegia and microcephaly.