"Iron"ing out hemophagocytosis through PIEZO1.

In this issue of Cell, Ma et al. reveal a mechanistic role for PIEZO1 in iron homeostasis through molecular genetic mouse studies. They also demonstrate implications for human iron overload and deficiency syndromes, susceptibility to malarial infection, and red blood cell turnover in persons of African ancestries.

The 2023 Distinguished Speakers Symposium: Closing Remarks.

Highlighting the Distinguished Speakers Symposium on "The Future of Human Genetics and Genomics," this collection of articles is based on presentations at the ASHG 2023 Annual Meeting in Washington, DC, in celebration of all our field has accomplished in the past 75 years, since the founding of ASHG in 1948.

The African Society of Human Genetics successfully launches global data science workshops.

To accelerate the impact of African genomics on human health, data science skills and awareness of Africa's rich genetic diversity must be strengthened globally. We describe the first African genomics data science workshop, implemented by the African Society of Human Genetics (AfSHG) and international partners, providing a framework for future workshops.

The road ahead in genetics and genomics.

In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone.

Genome-wide association study identifies novel candidate malaria resistance genes in Cameroon.

Recent data suggest that only a small fraction of severe malaria heritability is explained by the totality of genetic markers discovered so far. The extensive genetic diversity within African populations means that significant associations are likely to be found in Africa. In their series of multi-site genome-wide association studies (GWAS) across sub-Saharan Africa, the Malaria Genomic Epidemiology Network (MalariaGEN) observed specific limitations and encouraged country-specific analyses. Here, we present findings of a GWAS of Cameroonian participants that contributed to MalariaGEN projects (n = 1103). We identified protective associations at polymorphisms within the enhancer region of CHST15 [Benjamin-Hochberg false discovery rate (FDR) < 0.02] that are specific to populations of African ancestry, and that tag strong eQTLs of CHST15 in hepatic cells. In-silico functional analysis revealed a signature of epigenetic regulation of CHST15 that is preserved in populations in historically malaria endemic regions, with haplotype analysis revealing a haplotype that is specific to these populations. Association analysis by ethnolinguistic group identified protective associations within SOD2 (FDR < 0.04), a gene previously shown to be significantly induced in pre-asymptomatic malaria patients from Cameroon. Haplotype analysis revealed substantial heterogeneity within the beta-like globin (HBB) gene cluster amongst the major ethnic groups in Cameroon confirming differential malaria pressure and underscoring age-old fine-scale genetic structure within the country. Our findings revealed novel insights in the evolutionary genetics of populations living in Cameroon under malaria pressure with new significant protective loci (CHST15 and SOD2) and emphasized the significant attenuation of genetic association signals by fine-scale genetic structure.

Five Priorities of African Genomics Research: The Next Frontier.

To embrace the prospects of accurately diagnosing thousands of monogenic conditions, predicting disease risks for complex traits or diseases, tailoring treatment to individuals' pharmacogenetic profiles, and potentially curing some diseases, research into African genomic variation is a scientific imperative. African genomes harbor millions of uncaptured variants accumulated over 300,000 years of modern humans' evolutionary history, with successive waves of admixture, migration, and natural selection combining with extensive ecological diversity to create a broad and exceptional genomic complexity. Harnessing African genomic complexity, therefore, will require sustained commitment and equitable collaboration from the scientific community and funding agencies. African governments must support academic public research and industrial partnerships that build the necessary genetic medicine workforce, utilize the emerging genomic big data to develop expertise in computer science and bioinformatics, and evolve national and globalgovernance frameworks that recognize the ethical implications of data-driven genomic research and empower its application in African social, cultural, economic, and religious contexts.

Caught between pity, explicit bias, and discrimination: a qualitative study on the impact of stigma on the quality of life of persons living with sickle cell disease in three African countries.

PURPOSE: Sickle cell disease (SCD) is an inherited blood disorder characterized by unpredictable episodes of acute pain and numerous health complications. Individuals with SCD often face stigma from the public, including perceptions that they are lazy or weak tending to exaggerate their pain crisis, which can profoundly impact their quality of life (QoL). METHODS: In a qualitative phenomenological study conducted in Cameroon, Ghana, and Tanzania, we explored stakeholders' perceptions of SCD-related stigma using three analytical frameworks: Bronfenbrenner's Ecological Systems Theory; The Health Stigma and Discriminatory Framework; and A Public Health Framework for Reducing Stigma. RESULTS: The study reveals that SCD-related stigma is marked by prejudice, negative labelling and social discrimination, with derogatory terms such as sickler, ogbanje (one who comes and goes), sika besa (money will finish), ene mewu (I can die today, I can die tomorrow), vampire (one who consumes human blood), and Efiewura (landlord-of the hospital), commonly used to refer to individuals living with SCD. Drivers of stigma include frequent crises and hospitalizations, distinct physical features of individuals living with SCD, cultural misconceptions about SCD and its association with early mortality. Proposed strategies for mitigating stigma include public health education campaigns about SCD, integrating SCD into school curricula, healthcare worker training and community engagement. CONCLUSION: The results highlight the importance of challenging stigmatizing narratives on SCD and recognizing that stigmatization represents a social injustice that significantly diminishes the QoL of individuals living with SCD.

Perspectives of researchers, science policy makers and research ethics committee members on the feedback of individual genetic research findings in African genomics research.

BACKGROUND: Genetic research can yield information that is unrelated to the study's objectives but may be of clinical or personal interest to study participants. There is an emerging but controversial responsibility to return some genetic research results, however there is little evidence available about the views of genomic researchers and others on the African continent. METHODS: We conducted a continental survey to solicit perspectives of researchers, science policy makers and research ethics committee members on the feedback of individual genetic research findings in African genomics research. RESULTS: A total of 110 persons participated in the survey with 51 complete and 59 incomplete surveys received. Data was summarised using descriptive analysis. Overall, our respondents believed that individual genetic research results that are clinically actionable should be returned to study participants apparently because participants have a right to know things about their health, and it might also be a means for research participation to be recognized. Nonetheless, there is a need for development of precise guidance on how to return individual genetic research findings in African genomics research. DISCUSSION: Participants should receive information that could promote a healthier lifestyle; only clinically actionable findings should be returned, and participants should receive all important information that is directly relevant to their health. Nevertheless, detailed guidelines should inform what ought to be returned. H3Africa guidelines stipulate that it is generally considered good practice for researchers to feedback general study results, but there is no consensus about whether individual genomic study results should also be fed back. The decision on what individual results to feedback, if any, is very challenging and the specific context is important to make an appropriate determination.

Looking ahead: ethical and social challenges of somatic gene therapy for sickle cell disease in Africa.

Somatic gene therapy will be one of the most exciting practices of genetic medicine in Africa and is primed to offer a "new life" for persons living with sickle cell disease (SCD). Recently, successful gene therapy trials for SCD in the USA have sparked a ray of hope within the SCD community in Africa. However, the high cost, estimated to exceed 1.5 million USD, continues to be a major concern for many stakeholders. While affordability is a key global health equity consideration, it is equally important to reflect on other ethical, legal and social issues (ELSIs) that may impact the responsible implementation of gene therapy for SCD in Africa. These include informed consent comprehension, risk of therapeutic misestimation and optimistic bias; priorities for SCD therapy trials; dearth of ethical and regulatory oversight for gene therapy in many African countries; identifying a favourable risk-benefit ratio; criteria for the selection of trial participants; decisional conflict in consent; standards of care; bounded justice; and genetic tourism. Given these ELSIs, we suggest that researchers, pharma, funders, global health agencies, ethics committees, science councils and SCD patient support/advocacy groups should work together to co-develop: (1) patient-centric governance for gene therapy in Africa, (2) public engagement and education materials, and (3) decision making toolkits for trial participants. It is also critical to establish harmonised ethical and regulatory frameworks for gene therapy in Africa, and for global health agencies to accelerate access to basic care for SCD in Africa, while simultaneously strengthening capacity for gene therapy.

Evolutionary history of sickle-cell mutation: implications for global genetic medicine.

Resistance afforded by the sickle-cell trait against severe malaria has led to high frequencies of the sickle-cell mutation [HBB; c.20T>A, p.Glu6Val; OMIM: 141900 (HBB-ßS)] in most parts of Africa. High-coverage sequencing and genotype data have now confirmed the single African origin of the sickle-cell gene variant [HBB; c.20T>A, p.Glu6Val; OMIM: 141900 (HBB-ßS)]. Nevertheless, the classical HBB-like genes cluster haplotypes remain a rich source of HBB-ßS evolutionary information. The overlapping distribution of HBB-ßS and other disease-associated variants means that their evolutionary genetics must be investigated concurrently. In this review: (1) we explore the evolutionary history of HBB-ßS and its implications in understanding human migration within and out of Africa: e.g. HBB haplotypes and recent migration paths of the Bantu expansion, occurrence of ~7% of the Senegal haplotype in Angola reflecting changes in population/SCD dynamics, and existence of all five classical HBB haplotype in Cameroon and Egypt suggesting a much longer presence of HBB-ßS in these regions; (2) we discuss the time estimates of the emergence of HBB-ßS in Africa and finally, (3) we discuss implications for genetic medicine in understanding complex epistatic interactions between HBB-ßS and other gene variants selected under environmental pressure in Africa e.g. variants in HBB, HBA, G6PD, APOL1, APOE, OSBPL10 and RXRA.

Whole exome sequencing reveals pathogenic variants in MYO3A, MYO15A and COL9A3 and differential frequencies in ancestral alleles in hearing impairment genes among individuals from Cameroon.

There is scarcity of known gene variants of hearing impairment (HI) in African populations. This knowledge deficit is ultimately affecting the development of genetic diagnoses. We used whole exome sequencing to investigate gene variants, pathways of interactive genes and the fractions of ancestral overderived alleles for 159 HI genes among 18 Cameroonian patients with non-syndromic HI (NSHI) and 129 ethnically matched controls. Pathogenic and likely pathogenic (PLP) variants were found in MYO3A, MYO15A and COL9A3, with a resolution rate of 50% (9/18 patients). The study identified significant genetic differentiation in novel population-specific gene variants at FOXD4L2, DHRS2L6, RPL3L and VTN between HI patients and controls. These gene variants are found in functional/co-expressed interactive networks with other known HI-associated genes and in the same pathways with VTN being a hub protein, that is, focal adhesion pathway and regulation of the actin cytoskeleton (P-values <0.05). The results suggest that these novel population-specific gene variants are possible modifiers of the HI phenotypes. We found a high proportion of ancestral allele versus derived at low HI patients-specific minor allele frequency in the range of 0.0-0.1. The results showed a relatively low pickup rate of PLP variants in known genes in this group of Cameroonian patients with NSHI. In addition, findings may signal an evolutionary enrichment of some variants of HI genes in patients, as the result of polygenic adaptation, and suggest the possibility of multigenic influence on the phenotype of congenital HI, which deserves further investigations.

IHP-PING-generating integrated human protein-protein interaction networks on-the-fly.

Advances in high-throughput sequencing technologies have resulted in an exponential growth of publicly accessible biological datasets. In the 'big data' driven 'post-genomic' context, much work is being done to explore human protein-protein interactions (PPIs) for a systems level based analysis to uncover useful signals and gain more insights to advance current knowledge and answer specific biological and health questions. These PPIs are experimentally or computationally predicted, stored in different online databases and some of PPI resources are updated regularly. As with many biological datasets, such regular updates continuously render older PPI datasets potentially outdated. Moreover, while many of these interactions are shared between these online resources, each resource includes its own identified PPIs and none of these databases exhaustively contains all existing human PPI maps. In this context, it is essential to enable the integration of or combining interaction datasets from different resources, to generate a PPI map with increased coverage and confidence. To allow researchers to produce an integrated human PPI datasets in real-time, we introduce the integrated human protein-protein interaction network generator (IHP-PING) tool. IHP-PING is a flexible python package which generates a human PPI network from freely available online resources. This tool extracts and integrates heterogeneous PPI datasets to generate a unified PPI network, which is stored locally for further applications.

Variants of LRP2, encoding a multifunctional cell-surface endocytic receptor, associated with hearing loss and retinal dystrophy.

Hereditary deafness and retinal dystrophy are each genetically heterogenous and clinically variable. Three small unrelated families segregating the combination of deafness and retinal dystrophy were studied by exome sequencing (ES). The proband of Family 1 was found to be compound heterozygous for NM_004525.3: LRP2: c.5005A > G, p.(Asn1669Asp) and c.149C > G, p.(Thr50Ser). In Family 2, two sisters were found to be compound heterozygous for LRP2 variants, p.(Tyr3933Cys) and an experimentally confirmed c.7715 + 3A > T consensus splice-altering variant. In Family 3, the proband is compound heterozygous for a consensus donor splice site variant LRP2: c.8452_8452 + 1del and p.(Cys3150Tyr). In mouse cochlea, Lrp2 is expressed abundantly in the stria vascularis marginal cells demonstrated by smFISH, single-cell and single-nucleus RNAseq, suggesting that a deficiency of LRP2 may compromise the endocochlear potential, which is required for hearing. LRP2 variants have been associated with Donnai-Barrow syndrome and other multisystem pleiotropic phenotypes different from the phenotypes of the four cases reported herein. Our data expand the phenotypic spectrum associated with pathogenic variants in LRP2 warranting their consideration in individuals with a combination of hereditary hearing loss and retinal dystrophy.

Feeding back of individual genetic results in Botswana: mapping opportunities and challenges.

PURPOSE: We explored the views of Botswana stakeholders involved in developing, implementing and applying ethical standards for return of individual study results from genomic research. This allowed for mapping opportunities and challenges regarding actionability requirements that determine whether individual genomic research results should be fed back. METHODS: Using in-depth interviews, this study explored the views of sixteen (16) stakeholders about the extent, nature and timing of feedback of individual genomic research findings, including incidental findings that arise in the context of African genomics research. Coded data was analyzed through an iterative process of analytic induction to document and interpret themes. RESULTS: Overall, respondents were of the view that feedback of actionable individual genomic results was an important outcome that could benefit participants. However, a number of themes surfaced that pointed to opportunities and challenges that exist in Botswana that could help in planning for feeding back of individual genomic results that were mapped. Some of the opportunities cited by the respondents included the existence of good governance; democracy and humanitarianism; universal healthcare system; national commitment to science; research and innovation to transform Botswana into a knowledge-based economy; and applicable standard of care which could promote actionability. On the other hand, contextual issues like the requirement for validation of genomic research results in accredited laboratories, high cost of validation of genomic results, and linkage to care, as well as lack of experts like genomic scientists and counselors were considered as challenges for return of individual results. CONCLUSION: We propose that decisions whether and which genomic results to return take into consideration contextual opportunities and challenges for actionability for return of results in a research setting. This is likely to avoid or minimize ethical issues of justice, equity and harm regarding actionability decisions.

Addressing exploitation and inequities in open science: A relational perspective.

There are concerns that participation in open science will lead to various forms of exploitation - of researchers and scholars in low-income countries and under-resourced institutions. This article defends a contrary thesis and demonstrates the exact ways the underexplored notions of communal relationships, human dignity and social justice - and the normative principles to which they give rise - grounded in African philosophy can usefully address critical concerns regarding exploitation in the sharing of research resources to facilitate open partnership/collaboration and reuse. Further research is required to study the specific roles different institutions can play in facilitating open practice and contribute towards establishing effective structures that can enhance equity and balance unfavourable power asymmetries.

Hearing loss in Africa: current genetic profile.

Hearing impairment (HI) is highly heterogeneous with over 123 associated genes reported to date, mostly from studies among Europeans and Asians. Here, we performed a systematic review of literature on the genetic profile of HI in Africa. The study protocol was registered on PROSPERO, International Prospective Register of Systematic Reviews with the registration number "CRD42021240852". Literature search was conducted on PubMed, Scopus, Africa-Wide Information, and Web of Science databases. A total of 89 full-text records was selected and retrieved for data extraction and analyses. We found reports from only 17/54 (31.5%) African countries. The majority (61/89; 68.5%) of articles were from North Africa, with few reports found from sub-Saharan Africa. The most common method used in these publications was targeted gene sequencing (n = 66/111; 59.5%), and only 13.5% (n = 15/111) used whole-exome sequencing. More than half of the studies were performed in families segregating HI (n = 51/89). GJB2 was the most investigated gene, with GJB2: p.(R143W) founder variant only reported in Ghana, while GJB2: c.35delG was common in North African countries. Variants in MYO15A were the second frequently reported in both North and Central Africa, followed by ATP6V1B1 only reported from North Africa. Usher syndrome was the main syndromic HI molecularly investigated, with variants in five genes reported: USH2A, USH1G, USH1C, MYO7A, and PCDH15. MYO7A: p.(P1780S) founder variant was reported as the common Usher syndrome variant among Black South Africans. This review provides the most comprehensive data on HI gene variants in the largely under-investigated African populations. Future exomes studies particularly in multiplex families will likely provide opportunities for the discovery of the next sets of novel HI genes, and well as unreported variants in known genes to further our understanding of HI pathobiology, globally.

Current profile of Charcot-Marie-Tooth disease in Africa: A systematic review.

BACKGROUND AND AIMS: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy characterised by a high clinical and genetic heterogeneity. While most cases were described in populations with Caucasian ancestry, genetic research on CMT in Africa is scant. Only a few cases of CMT have been reported, mainly from North Africa. The current study aimed to summarise available data on CMT in Africa, with emphasis on the epidemiological, clinical, and genetic features. METHODS: We searched PubMed, Scopus, Web of Sciences, and the African Journal Online for articles published from the database inception until April 2021 using specific keywords. A total of 398 articles were screened, and 28 fulfilled our selection criteria. RESULTS: A total of 107 families totalling 185 patients were reported. Most studies were reported from North Africa (n = 22). The demyelinating form of CMT was the commonest subtype, and the phenotype varied greatly between families, and one family (1%) of CMT associated with hearing impairment was reported. The inheritance pattern was autosomal recessive in 91.2% (n = 97/107) of families. CMT-associated variants were reported in 11 genes: LMNA, GDAP1, GJB1, MPZ, MTMR13, MTMR2, PRX, FGD4/FRABIN, PMP22, SH3TC2, and GARS. The most common genes reported are LMNA, GDAP1, and SH3TC2 and have been found mostly in Northern African populations. INTERPRETATION: This study reveals that CMT is not rare in Africa, and describes the current clinical and genetic profile. The review emphasised the urgent need to invest in genetic research to inform counselling, prevention, and care for CMT in numerous settings on the continent.