The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Génétique des surdités héréditaires au sein de la population marocaine : étude des gènes MPZL2, CO4A3, MASP1 et ELMOD2

Hearing, mediated by the ear, if impaired results in deafness of varying degrees affecting some 430 million people with moderate to severe hearing loss. This neurosensory disability is caused by environmental factors and genetic defects. The search for new pathogenic genetic determinants responsible for syndromic and non-syndromic deafness in the Moroccan population was the main objective of this work, allowing a better understanding of its heterogeneity. Genetic analysis conducted on a family with non-syndromic deafness revealed the c.72delA variant of MPZL2. For syndromic deafness, we identified pathogenic variants in COL4A3 in two brothers with the Alport syndrome, and in MASP1 in an individual with the 3MC syndrome. We also identifieda homozygous variant in ELMOD2, encoding a GAP involved in mitochondrial dynamics and ciliogenesis, found for the first time in two patients with hearing loss and autism spectrum disorders. The analysis of the mitochondrial network of the patient and his healthy mother disclosed an alteration of the mitochondrial network fusion. We confirmed that GJB2variants remain responsible for most of the recessive non-syndromic deafness in Moroccan patients with 36,8% followed by LRTOMT variants, with a frequency of 8,63%. Together, these results contribute to the improvement of the knowledge on hereditary deafness in Morocco, as well as an improvement of the molecular diagnosis, opening novel opportunities to treat patients with emerging gene therapies.L’audition, le sens médié par l’oreille, si altéré abouti à une surdité de différent degré, affectant quelques 430 millions de personnes souffrant de surdité moyenne à sévère. Ce handicap neurosensoriel est causé par des facteurs environnementaux et des défauts génétiques. La recherche de nouveaux déterminants génétiques pathogènes responsables des surdités syndromiques et non syndromiques au sein de la population marocaine a été l’objectif principal de ces travaux de thèse permettant de mieux cerner son hétérogénéité. L’analyse génétique mené sur une famille atteinte d’une surdité non syndromique a révélé le variant c.72delA MPZL2. Pour les surdités syndromiques, nous avons identifié des variants pathogènes de COL4A3 chez deux frères atteints du syndrome d'Alport et de MASP1 chez un cas atteint du syndrome 3MC. Nous avons aussi mis en évidence une mutation homozygote d’ELMOD2, codant une GAP impliquée dans la dynamique mitochondriale et la ciliogenèse, retrouvé pour la première fois chez deux patients avec surdité et troubles du spectre autistique. L’analyse du réseau mitochondrial du patient et de sa mère suggère une légère altération de la fusion du réseau mitochondrial. Nous avons confirmé que les variants GJB2 restent responsables de la majeure partie des surdités non syndromiques récessives chez les patients marocains avec 36,8%, suivie de LRTOMT avec une fréquence de 8,63%. L’ensemble de ces résultats contribuent à l’amélioration des connaissances sur les surdités héréditaires au Maroc, ainsi qu’à l’ouverture vers un meilleur diagnostic moléculaire et la possibilité de traitements par les thérapies géniques émergentes

Genetic of hereditary deafness in the moroccan population : study of the genes MPZL2, CO4A3, MASP1 and ELMOD2

L’audition, le sens médié par l’oreille, si altéré abouti à une surdité de différent degré, affectant quelques 430 millions de personnes souffrant de surdité moyenne à sévère. Ce handicap neurosensoriel est causé par des facteurs environnementaux et des défauts génétiques. La recherche de nouveaux déterminants génétiques pathogènes responsables des surdités syndromiques et non syndromiques au sein de la population marocaine a été l’objectif principal de ces travaux de thèse permettant de mieux cerner son hétérogénéité. L’analyse génétique mené sur une famille atteinte d’une surdité non syndromique a révélé le variant c.72delA MPZL2. Pour les surdités syndromiques, nous avons identifié des variants pathogènes de COL4A3 chez deux frères atteints du syndrome d'Alport et de MASP1 chez un cas atteint du syndrome 3MC. Nous avons aussi mis en évidence une mutation homozygote d’ELMOD2, codant une GAP impliquée dans la dynamique mitochondriale et la ciliogenèse, retrouvé pour la première fois chez deux patients avec surdité et troubles du spectre autistique. L’analyse du réseau mitochondrial du patient et de sa mère suggère une légère altération de la fusion du réseau mitochondrial. Nous avons confirmé que les variants GJB2 restent responsables de la majeure partie des surdités non syndromiques récessives chez les patients marocains avec 36,8%, suivie de LRTOMT avec une fréquence de 8,63%. L’ensemble de ces résultats contribuent à l’amélioration des connaissances sur les surdités héréditaires au Maroc, ainsi qu’à l’ouverture vers un meilleur diagnostic moléculaire et la possibilité de traitements par les thérapies géniques émergentes.Hearing, mediated by the ear, if impaired results in deafness of varying degrees affecting some 430 million people with moderate to severe hearing loss. This neurosensory disability is caused by environmental factors and genetic defects. The search for new pathogenic genetic determinants responsible for syndromic and non-syndromic deafness in the Moroccan population was the main objective of this work, allowing a better understanding of its heterogeneity. Genetic analysis conducted on a family with non-syndromic deafness revealed the c.72delA variant of MPZL2. For syndromic deafness, we identified pathogenic variants in COL4A3 in two brothers with the Alport syndrome, and in MASP1 in an individual with the 3MC syndrome. We also identifieda homozygous variant in ELMOD2, encoding a GAP involved in mitochondrial dynamics and ciliogenesis, found for the first time in two patients with hearing loss and autism spectrum disorders. The analysis of the mitochondrial network of the patient and his healthy mother disclosed an alteration of the mitochondrial network fusion. We confirmed that GJB2variants remain responsible for most of the recessive non-syndromic deafness in Moroccan patients with 36,8% followed by LRTOMT variants, with a frequency of 8,63%. Together, these results contribute to the improvement of the knowledge on hereditary deafness in Morocco, as well as an improvement of the molecular diagnosis, opening novel opportunities to treat patients with emerging gene therapies

Novel pathogenic WHRN variant causing hearing loss in a moroccan family

International audienceThe most prevalent sensory disease in humans is deafness. A variety of genes have been linked to hearing loss, which can either be isolated (non-syndromic) or associated with lesions in other organs (syndromic). It has been discovered that WHRN variants are responsible for non-syndromic hearing loss and Usher syndrome type II

Homozygous Missense Variants in FOXI1 and TMPRSS3 Genes Associated with Non-syndromic Deafness in Moroccan Families

International audienceOne of the most prevalent sensorineural disorders, autosomal recessive non-syndromic hearing loss (ARNSHL) which can affect all age groups, from the newborn (congenital) to the elderly (presbycusis). Important etiologic, phenotypic, and genotypic factors can cause deafness. So far, the high genetic variability that explains deafness makes molecular diagnosis challenging. In Morocco, the GJB2 gene is the primary cause of non-syndromic hereditary deafness, while the existence of a variant in the LRTOMT gene is the second cause of this condition. After excluding these two frequently occurring GJB2 and LRTOMT variants, whole-exome sequencing was carried out in two Moroccan consanguineous families with hearing loss. As a result, two novel variants in the TMPRSS3 (c.1078G>A, p. Ala 360Thr) and FOXI1 (c.6C>G, p. Ser 2Arg) genes have been discovered in deaf patients and the pathogenic effect has been anticipated by several bioinformatics and molecular modeling systems. For the first time, these variants are identified in the Moroccan population, showing the population heterogeneity and demonstrating the value of the WES in hearing loss diagnosis

Genetic heterogeneity in GJB2, COL4A3, ATP6V1B1 and EDNRB variants detected among hearing impaired families in Morocco

International audienceBackground: Deafness is the most prevalent human sensorineural defect. It may occur as a result of an external auditory canal involvement, or a deficiency in the sound conduction mechanism, or an impairment of the cochlea, the cochlear nerve or central auditory perception. The genetic causes are the most common, as approximately 70% of hearing disorders are of hereditary origin, divided into two groups, syndromic (associated with other symptoms) and no syndromic (isolated deafness).Methods: A whole exome sequencing was performed to identify the genetic cause of hearing loss in six Moroccan families and Sanger sequencing was used to validate mutations in these genes.The results: The results of four out of the six families revealed four genetic variants in the genes GJB2, COL4A3, ATP6V1B1 and EDNRB responsible for non-syndromic and syndromic hearing loss. Multiple Bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations.Conclusions: We identified in Moroccan deaf patients four homozygous mutations. These results show the importance of whole exome sequencing to identify pathogenic mutations in heterogeneous disorders with multiple genes responsible

Genetic heterogeneity in GJB2, COL4A3, ATP6V1B1 and EDNRB variants detected among hearing impaired families in Morocco

International audienceBackground: Deafness is the most prevalent human sensorineural defect. It may occur as a result of an external auditory canal involvement, or a deficiency in the sound conduction mechanism, or an impairment of the cochlea, the cochlear nerve or central auditory perception. The genetic causes are the most common, as approximately 70% of hearing disorders are of hereditary origin, divided into two groups, syndromic (associated with other symptoms) and no syndromic (isolated deafness).Methods: A whole exome sequencing was performed to identify the genetic cause of hearing loss in six Moroccan families and Sanger sequencing was used to validate mutations in these genes.The results: The results of four out of the six families revealed four genetic variants in the genes GJB2, COL4A3, ATP6V1B1 and EDNRB responsible for non-syndromic and syndromic hearing loss. Multiple Bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations.Conclusions: We identified in Moroccan deaf patients four homozygous mutations. These results show the importance of whole exome sequencing to identify pathogenic mutations in heterogeneous disorders with multiple genes responsible

A homozygous MPZL2 deletion is associated with non syndromic hearing loss in a moroccan family

International audienceAdhesion glycoproteins are implicated in the pathophysiology of hearing loss, the most frequent inherited sensory disorder, affecting 1 in 1000 new-borns. Exome sequencing of a consanguineous Moroccan patient with mild hearing loss identified for the first time in a North African family a single homozygous mutation c.72delA in MPZL2 gene, encoding the Myelin Protein Zero-Like 2, reported as causing deafness in two other populations. Variable tandem repeat genotyping of this family revealed that the c.72delA MPZL2 allele shared a common haplotype with Turkish and Dutch families. These results confirm the pathogenicity of this MPZL2 mutation in recessive mild to moderate non-syndromic deafness