H3Africa is developing capacity for health-related genomics research in Africa

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered. We implemented whole-genome sequencing (WGS) in a national healthcare system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank 1 , we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare. 3. Ferreira CR. The burden of rare diseases.

Discovery of most autosomal recessive disease genes has involved analysis of large, often consanguineous, multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of novel dominant causes of rare, genetically heterogenous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios 1,2. Here we analysed 4,125 families with diverse, rare, genetically heterogeneous developmental disorders and identified four novel autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (identifying probands with rare biallelic putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population, and (ii) the phenotypic similarity of patients with the same recessive candidate gene. This new paradigm promises to catalyse discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations, and those caused predominantly by compound heterozygous genotypes.

Depression is a leading cause of disability worldwide, but most depressed individuals do not receive treatment. There is now significant support for physical exercise as an effective alternative treatment for depression, which may be more accessible than traditional psychiatric treatments. Little is known about preferences for exercise as a depression treatment. Method A total of 102 individuals (50% female, mean age = 39 (SD=13.1; range: 18–62), 83% Caucasian) with likely major depression completed an online survey of exercise for depression treatment preferences and barriers to increased exercise. Results are reported by gender due to well established gender differences in exercise preferences. Results Both genders reported a high level of interest in an exercise for depression program. On average, participants preferred an individual walking program that was coached, asked them to engage in one longer bout multiple times per week, and was provided in home. However, there was significant variability within and between genders. Lack of motivation, mood, and fatigue were reported as barriers to exercise by the majority of participants of both genders. Conclusion The majority of those with depression have interest in an exercise for depression program, but symptoms of depression are seen as significant barriers. Future studies should use these results to design exercise for depression programs. The variability and gender differences in our results suggest that flexible programs may be needed.

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