3 research outputs found
The Dynamics of the Resistance Committees (RCs) Movement Amid the Current Challenges of Democratic Transition in Sudan
No full textAfter the wave of protests that led to the fall of the former regime in April 2019 and the establishment of the Transitional Justice in August 2019, Sudan is undergoing transitional phases marked by significant political and social changes since 2018. The Sudanese Resistance Committees (RCs) have played important and crucial roles throughout the whole period since the breakthrough of the Revolution in Sudan in December 2018. Those roles are showcased starting from organizing and mobilizing the protests that took place prior to the fall of the regime. The dynamics of the movement have developed since then due to the successive events in the course of the Sudanese Revolution. With every stage of the complex political transitions and shifts in Sudan thereafter, RCs were playing major roles that effectively kept pace with the course of events, enabling them to play decisive roles such as massive marches amidst the disruption of communication and internet services after the General Command of the Army sit-in dispersal
Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy
No full textPurpose: Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder. Methods: Exome sequencing and rare variant family-based genomics was performed as a part of the Baylor-Hopkins Center for Mendelian Genomics Initiative. Additional families were identified via GeneMatcher. Results: We identified six patients from three unrelated families with homozygous loss-of-function variants in NSRP1. Clinical features include developmental delay, epilepsy, variable microcephaly (Z-scores �0.95 to �5.60), hypotonia, and spastic cerebral palsy. Brain abnormalities included simplified gyral pattern, underopercularization, and/or vermian hypoplasia. Molecular analysis identified three pathogenic NSRP1 predicted loss-of-function variant alleles: c.13591362delAAAG (p.Glu455AlafsTer20), c.1272dupG (p.Lys425GlufsTer5), and c.52C>T (p.Gln18Ter). The two frameshift variants result in a premature termination codon in the last exon, and the mutant transcripts are predicted to escape nonsense mediated decay and cause loss of a C-terminal nuclear localization signal required for NSRP1 function. Conclusion: We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics
Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders
No full textMED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Utilizing exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17±12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinestic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterised by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%), and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%), and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations, and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of "neuro-MEDopathies".</p
