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BACKGROUND: Chromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty. RESULTS: We identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene. CONCLUSION: This report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.
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Deleção Cromossômica , Cromossomos Humanos Par 16 , Síndrome de Dandy-Walker , Microcefalia , Fenótipo , Humanos , Cromossomos Humanos Par 16/genética , Microcefalia/genética , Microcefalia/patologia , Microcefalia/complicações , Feminino , Síndrome de Dandy-Walker/genética , Síndrome de Dandy-Walker/complicações , Síndrome de Dandy-Walker/patologia , Variações do Número de Cópias de DNA/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Criança , Masculino , Arábia Saudita , Pré-Escolar , Transtorno AutísticoRESUMO
ATPase, class 1, type 8 A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings born from a consanguineous, first-cousin union from Sudan presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.
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Machado-Joseph disease (MJD/SCA3) is the most frequent dominant ataxia worldwide. It is caused by a (CAG)n expansion. MJD has two major ancestral backgrounds: the Machado lineage, found mainly in Portuguese families; and the Joseph lineage, present in all five continents, probably originating in Asia. MJD has been described in a few African and African-American families, but here we report the first diagnosed in Sudan to our knowledge. The proband presented with gait ataxia at age 24; followed by muscle cramps and spasticity, and dysarthria, by age 26; he was wheel-chair bound at 29 years of age. His brother had gait problems from age 20 years and, by age 21, lost the ability to run, showed dysarthria and muscle cramps. To assess the mutational origin of this family, we genotyped 30 SNPs and 7 STRs flanking the ATXN3_CAG repeat in three siblings and the non-transmitting father. We compared the MJD haplotype segregating in the family with our cohort of MJD families from diverse populations. Unlike all other known families of African origin, the Machado lineage was observed in Sudan, being shared with 86 Portuguese, 2 Spanish and 2 North-American families. The STR-based haplotype of Sudanese patients, however, was distinct, being four steps (2 STR mutations and 2 recombinations) away from the founder haplotype shared by 47 families, all of Portuguese extraction. Based on the phylogenetic network constructed with all MJD families of the Machado lineage, we estimated a common ancestry at 3211 ± 693 years ago.
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Doença de Machado-Joseph , Masculino , Humanos , Adulto Jovem , Adulto , Doença de Machado-Joseph/genética , Doença de Machado-Joseph/diagnóstico , Portugal , Cãibra Muscular , Disartria , Filogenia , África OrientalRESUMO
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.
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Adenosina Desaminase , Deficiência Intelectual , Proteínas de Ligação a RNA , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Adenosina Desaminase/genética , Exoma , Humanos , Deficiência Intelectual/diagnóstico , Microcefalia/genética , Mutação , Paraplegia/genética , Linhagem , Fenótipo , Proteínas de Ligação a RNA/genética , Sudão , Proteínas Supressoras de Tumor/genética , Tunísia , Ubiquitina-Proteína Ligases/genética , Sequenciamento do ExomaRESUMO
Mutations in MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare form of leukodystrophy characterized by macrocephaly, epilepsy, spasticity, and slow mental deterioration. Genetic studies of MLC are lacking from many parts of the world, especially in Sub-Saharan Africa. Genomic DNA was extracted for 67 leukodystrophic patients from 43 Sudanese families. Mutations were screened using the NGS panel testing 139 leukodystrophies and leukoencephalopathies causing genes (NextSeq500 Illumina). Five homozygous MLC1 variants were discovered in seven patients from five distinct families, including three consanguineous families from the same region of Sudan. Three variants were missense (c.971 T > G, p.Ile324Ser; c.344 T > C, p.Phe115Ser; and c.881 C > T, p.Pro294Leu), one duplication (c.831_838dupATATCTGT, p.Ser280Tyrfs*8), and one synonymous/splicing-site mutation (c.762 C > T, p.Ser254). The segregation pattern was consistent with autosomal recessive inheritance. The clinical presentation and brain MRI of the seven affected patients were consistent with the diagnosis of MLC1. Due to the high frequency of distinct MLC1 mutations found in our leukodystrophic Sudanese families, we analyzed the coding sequence of MLC1 gene in 124 individuals from the Sudanese genome project in comparison with the 1000-genome project. We found that Sudan has the highest proportion of deleterious variants in MLC1 gene compared with other populations from the 1000-genome project.
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Cistos , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Megalencefalia , Cistos/diagnóstico , Cistos/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Humanos , Proteínas de Membrana/genética , MutaçãoRESUMO
PRUNE1 is linked to a wide range of neurodevelopmental and neurodegenerative phenotypes. Multiple pathogenic missense and stop-gain PRUNE1 variants were identified in its DHH and DHHA2 phosphodiesterase domains. Conversely, a single splice alteration was previously reported. We investigated five patients from two unrelated consanguineous Sudanese families with an inherited severe neurodevelopmental disorder using whole-exome sequencing coupled with homozygosity mapping, segregation, and haplotype analysis. We identified a founder haplotype transmitting a homozygous canonical splice-donor variant (NM_021222.3:c.132+2T > C) in intron 2 of PRUNE1 segregated with the phenotype in all the patients. This splice variant possibly results in an in-frame deletion in the DHH domain or premature truncation of the protein. The phenotypes of the affected individuals showed phenotypic similarities characterized by remarkable pyramidal dysfunction and prominent extrapyramidal features (severe dystonia and bradykinesia). In conclusion, we identified a novel founder variant in PRUNE1 and corroborated abnormal splicing events as a disease mechanism in PRUNE1-related disorders. Given the phenotypes' consistency coupled with the founder effect, canonical and cryptic PRUNE1 splice-site variants should be carefully evaluated in patients presenting with prominent dystonia and pyramidal dysfunction.
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Distonia/genética , Hipocinesia/genética , Transtornos do Neurodesenvolvimento/genética , Monoéster Fosfórico Hidrolases/genética , Splicing de RNA , Criança , Pré-Escolar , Consanguinidade , Feminino , Haplótipos , Homozigoto , Humanos , Íntrons , Masculino , Linhagem , Fenótipo , Sítios de Splice de RNA , Sudão , Sequenciamento do ExomaRESUMO
BACKGROUND: CCDC88C is a ubiquitously expressed protein with multiple functions, including roles in cell polarity and the development of dendrites in the nervous system. Bi-allelic mutations in the CCDC88C gene cause autosomal recessive congenital hydrocephalus (OMIM #236600). Studies recently linked heterozygous mutations in CCDC88C to the development of the late-onset spinocerebellar ataxia type 40 (OMIM #616053). CASE PRESENTATION: A 48-year-old Sudanese female presented with pure early onset hereditary spastic paraplegia. Exome sequencing, in-silico analysis, and Sanger sequencing identified the heterozygous NM_001080414.4:c.1993G > A (p.E665K) variant in CCDC88C as a potential cause of her illness. To explore the pathogenicity of the NM_001080414.4:c.1993G > A (p.E665K) variant, we expressed it in human embryonic kidney 293 cells and assessed its effects on apoptosis. In our experiment, NM_001080414.4:c.1993G > A (p.E665K) induced JNK hyper-phosphorylation and enhanced apoptosis. In contrast to previous reports, our patient developed neurological symptoms in early childhood and showed neither features of cerebellar ataxia, extrapyramidal signs, nor evidence of intellectual involvement. CONCLUSION: We, herein, heighlighted the possibility of extending the phenotype associated with variants in CCDC88C to include early-onset pure hereditary spastic paraplegia.
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Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas dos Microfilamentos/genética , Paraplegia Espástica Hereditária/genética , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , MutaçãoRESUMO
Genetic mutations associated with brain malformations can lead to a spectrum of severity and it is often difficult to determine whether there are additional pathogenic variants contributing to the phenotype. Here, we present a family affected by a severe brain malformation including bilateral polymicrogyria, hydrocephalus, patchy white matter signal changes, and cerebellar and pontine hypoplasia with elongated cerebellar peduncles leading to the molar tooth sign. While the malformation is reminiscent of bilateral frontoparietal polymicrogyria (BFPP), the phenotype is more severe than previously reported and also includes features of Joubert syndrome (JBTS). Via exome sequencing, we identified homozygous truncating mutations in both ADGRG1/GPR56 and KIAA0556, which are known to cause BFPP and mild brain-specific JBTS, respectively. This study shows how two independent mutations can interact leading to complex brain malformations.
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Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Hidrocefalia/genética , Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Polimicrogiria/genética , Receptores Acoplados a Proteínas G/genética , Retina/anormalidades , Criança , Exoma , Saúde da Família , Feminino , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/patologia , Mutação , Linhagem , Fenótipo , Prosencéfalo/patologia , Análise de Sequência de DNA , Sudão , Substância Branca/patologia , Sequenciamento do Exoma , Adulto JovemRESUMO
BACKGROUND: Infantile neuroaxonal dystrophy (INAD) is a rare hereditary neurological disorder caused by mutations in PLA2G6. The disease commonly affects children below 3 years of age and presents with delay in motor skills, optic atrophy and progressive spastic tetraparesis. Studies of INAD in Africa are extremely rare, and genetic studies from Sub Saharan Africa are almost non-existent. CASE PRESENTATION: Two Sudanese siblings presented, at ages 18 and 24 months, with regression in both motor milestones and speech development and hyper-reflexia. Brain MRI showed bilateral and symmetrical T2/FLAIR hyperintense signal changes in periventricular areas and basal ganglia and mild cerebellar atrophy. Whole exome sequencing with confirmatory Sanger sequencing were performed for the two patients and healthy family members. A novel variant (NM_003560.2 c.1427 + 2 T > C) acting on a splice donor site and predicted to lead to skipping of exon 10 was found in PLA2G6. It was found in a homozygous state in the two patients and homozygous reference or heterozygous in five healthy family members. CONCLUSION: This variant has one very strong (loss of function mutation) and three supporting evidences for its pathogenicity (segregation with the disease, multiple computational evidence and specific patients' phenotype). Therefore this variant can be currently annotated as "pathogenic". This is the first study to report mutations in PLA2G6 gene in patients from Sudan.
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Sequenciamento do Exoma/métodos , Fosfolipases A2 do Grupo VI/genética , Mutação , Distrofias Neuroaxonais/genética , Sítios de Splice de RNA , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Humanos , Lactente , Masculino , Irmãos , SudãoRESUMO
BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM #611105) is a genetic disease of the central nervous system characterized by lower limb spasticity, cerebellar ataxia and involvement of the dorsal column. The disease is caused by mutations in the DARS2 gene but has never been reported in sub-Saharan Africa so far. CASE PRESENTATION: Two siblings, aged 18 years and 15 years, from a consanguineous family presented with pyramidal signs and symptoms since infancy and developmental delay. Whole exome sequencing of the proband identified two compound heterozygous variants (NM_018122.4:c.1762C > G and c.563G > A) in DARS2. Sanger sequencing confirmed the presence of the mutations and their segregation in trans in both patients and in their elder sister (aged 20 years), who showed only brisk reflexes and mild lower limb spasticity. Surprisingly, in contrast to her subtle clinical presentation, the elder sister had abnormal MRI features and serum lactate levels comparable to her ill sisters. CONCLUSION: This report illustrates intra-familial phenotypic variation in LBSL and provides an example of a marked dissociation between the clinical and radiological phenotypes of the disease. This may have implications for the detection of mutation carriers in LBSL.
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Aspartato-tRNA Ligase/genética , Leucoencefalopatias/genética , Adolescente , Feminino , Humanos , Mutação , Linhagem , Fenótipo , Irmãos , Sudão , Adulto JovemRESUMO
Background: Despite the widespread practice of consanguinity in Sudan, there is a lack of exploration into the community's awareness of its health implications on offspring and their overall attitude towards consanguineous unions. Aim: This study aimed to evaluate the community's awareness of the possible health adversities of consanguinity on children and assess the effect of knowledge level on the prevailing attitude towards this practice in Sudan. Methods: From August to December 2018, data were collected from adults aged 18 years and above in five provinces of Sudan regardless of their marital status. The analysis involved both descriptive and multivariate statistical techniques. Results: This study revealed a consanguinity rate of 30.2%. Despite a high awareness level (73.7%) regarding the effects of consanguineous marriage on the health of the offspring, a moderately negative attitude towards this practice (63.9%) was observed. Conclusion: The discordance between the high consanguinity rate in the Sudanese population and the moderately negative attitude suggests a potential persistence of this practice in the future. Without the implementation of educational programs and the provision of genetic counselling services to consanguineous couples, the prevalence of consanguinity is likely to endure.
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ATPase, class 1, type 8A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.
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Heterozygous PRRT2 variants are frequently implicated in Self-limited Infantile Epilepsy, whereas homozygous variants are so far linked to severe presentations including developmental and epileptic encephalopathy, movement disorders, and intellectual disability. In a study aiming to explore the genetics of epilepsy in the Sudanese population, we investigated several families including a consanguineous family with three siblings diagnosed with self-limited infantile epilepsy. We evaluated both dominant and recessive inheritance using whole exome sequencing and genomic arrays. We identified a pathogenic homozygous splice-site variant in the first intron of PRRT2 [NC_000016.10(NM_145239.3):c.-65-1G > A] that segregated with the phenotype in this family. This work taps into the genetics of epilepsy in an underrepresented African population and suggests that the phenotypes of homozygous PRRT2 variants may include milder epilepsy presentations without movement disorders.
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INTRODUCTION: The phospholipase A2 group VI gene (PLA2G6) encodes an enzyme that catalyzes the hydrolytic release of fatty acids from phospholipids. Four neurological disorders with infantile, juvenile, or early adult-onset are associated with PLA2G6 genetic alterations, namely infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia-parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). Few studies in Africa reported PLA2G6-associated disorders and none with parkinsonism of late adult onset. MATERIAL AND METHODS: The patients were clinically assessed following UK Brain Bank diagnostic criteria and International Parkinson and Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Brain MRI without contrast was performed. Genetic testing was done using a custom-made Twist panel, screening 34 known genes, 27 risk factors, and 8 candidate genes associated with parkinsonism. Filtered variants were PCR-amplified and validated using Sanger sequencing and also tested in additional family members to study their segregation. RESULT: Two siblings born to consanguineous parents developed parkinsonism at the age of 58 and 60 years, respectively. MRI showed an enlarged right hippocampus in patient 2, but no overt abnormalities indicative of INAD or iron deposits. We found two heterozygous variants in PLA2G6, an in-frame deletion NM_003560:c.2070_2072del (p.Val691del) and a missense variant NM_003560:c.956C>T (p.Thr319Met). Both variants were classified as pathogenic. CONCLUSION: This is the first case in which PLA2G6 is associated with late-onset parkinsonism. Functional analysis is needed to confirm the dual effect of both variants on the structure and function of iPLA2ß.
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Distonia , Distúrbios Distônicos , Transtornos Parkinsonianos , Adulto , Humanos , Pessoa de Meia-Idade , Distonia/genética , Distúrbios Distônicos/genética , Testes Genéticos , Fosfolipases A2 do Grupo VI/genética , Mutação , Transtornos Parkinsonianos/genéticaRESUMO
PINK1 is the second most predominant gene associated with autosomal recessive Parkinson's disease. Homozygous mutations in this gene are associated with an early onset of symptoms. Bradykinesia, tremors, and rigidity are common features, while dystonia, motor fluctuation, and non-motor symptoms occur in a lower percentage of cases and usually respond well to levodopa. We investigated 14 individuals with parkinsonism and eleven symptom-free siblings from three consanguineous Sudanese families, two of them multigenerational, using a custom gene panel screening 34 genes, 27 risk variants, and 8 candidate genes associated with parkinsonism. We found a known pathogenic nonsense PINK1 variant (NM_032409.3:c.1366C>T; p.(Gln456*)), a novel pathogenic single base duplication (NM_032409.3:c.1597dup; p.(Gln533Profs*29)), and another novel pathogenic insertion (NM_032409.3:c.1448_1449ins[1429_1443; TTGAG]; p.(Arg483Serfs*7)). All variants were homozygous and co-segregated in all affected family members. We also identified intrafamilial and interfamilial phenotypic heterogeneity associated with PINK1 mutations in these Sudanese cases, possibly reflecting the nature of the Sudanese population that has a large effective population size, which suggests a higher possibility of novel findings in monogenic and polygenic diseases in Sudan.
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Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Doença de Parkinson/genética , Sudão , Transtornos Parkinsonianos/genética , Homozigoto , Mutação/genética , Proteínas Quinases/genética , Idade de InícioRESUMO
Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52-59% (31-35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.
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BACKGROUND: The etiology of intellectual disabilities is diverse and includes both genetic and environmental factors. The genetic causes of intellectual disabilities range from chromosomal aberrations to single gene disorders. The TRAPPC9 gene has been reported to cause autosomal recessive forms of intellectual disabilities in 56 patients from consanguineous and non-consanguineous families around the world. METHODS: We analyzed two siblings with intellectual disability, microcephaly and delayed motor and speech development from a consanguineous Sudanese family. Genomic DNA was screened for mutations using NGS panel (NextSeq500 Illumina) testing 173 microcephaly associated genes in the Molecular Genetics service in Robert Debre hospital in Paris, France. RESULTS: A novel homozygous mutation (NM_031466.7 (TRAPPC9):c.2288dup, p. (Val764Glyfs*7) in exon 14 of TRAPPC9 gene was found in the two patients. The mutation was predicted to cause nonsense mediated decay (NSMD) using SIFT prediction tool. The variant has not been found in either gnomAD or Exac databases. Both parents were heterozygous (carriers) to the mutation. CONCLUSION: This is the first study to report patients with TRAPPC9-related disorder from Sub-Saharan Africa.
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Deficiência Intelectual , Microcefalia , Humanos , Deficiência Intelectual/genética , Microcefalia/genética , Proteínas de Transporte/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , LinhagemRESUMO
Pontocerebellar hypoplasia type 10 (PCH10) is a very rare autosomal recessive neurodegenerative disease characterized by intellectual disability, microcephaly, severe developmental delay, pyramidal signs, mild cerebellar atrophy, and white matter changes in the brain, as shown by magnetic resonance imaging (MRI). The disease has been described in only twenty-one patients from ten Turkish families with a founder missense pathogenic variant in the CLP1 gene involved in tRNA processing and maturation. We analyzed three siblings from a consanguineous Sudanese family who presented with intellectual disability, dysmorphic features, developmental delay, regression of milestones, microcephaly, epilepsy, extrapyramidal signs, mild pontine, and cerebellar atrophy. We identified through whole-exome sequencing the same pathogenic variant (c.419G>A; p(Arg140His) reported before in all Turkish families. Our study extends the phenotypes of PCH10 and reports for the first time cases with PCH10 of non-Turkish origin.
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BACKGROUND: Several studies suggested a significant role of epigenetic changes, including alterations in miRNA, histone modifications, and DNA methylation of α-synuclein (SNCA) in Parkinson's disease (PD) pathogenicity. As of yet, only very few studies have been carried out in this field in Africa and none in Sudan. MATERIALS AND METHODS: We collected DNA from 172 Sudanese individuals (90 cases, 82 controls) who donated saliva for DNA extraction (mean age of onset: 40.6 ± 22.4 years). A family history of PD was evident in 64 patients. DNA preparation and bisulfite sequencing of SNCAintron1 was performed as described earlier. RESULTS: Of the fourteen analyzed CpGs of SNCAintron1, CpGs 16-23 were hypomethylated in PD (P-value ranged from 0.023 to 0.003). P-values improved, when sporadic cases were excluded from the analysis. CONCLUSION: We identified the presence of a specific pattern of DNA methylation in a young Sudanese cohort of familial PD, which confirms the importance of the methylation of SNCAintron1 for PD. This phenomenon appears to be independent of ethnicity, the impact of environmental factors, drug history, or familial clustering.