Guideline for feedback of individual genetic research findings for genomics research in Africa

As human genomics research in Africa continues to generate large amounts of data, ethical issues arise regarding how actionable genetic information is shared with research participants. The Human Heredity and Health in Africa Consortium (H3Africa) Ethics and Community Engagement Working group acknowledged the need for such guidance, identified key issues and principles relevant to genomics research in Africa and developed a practical guideline for consideration of feeding back individual genetic results of health importance in African research projects. This included a decision flowchart, providing a logical framework to assist in decision-making and planning for human genomics research projects. Although presented in the context of the H3Africa Consortium, we believe the principles described, and the decision flowchart presented here is applicable more broadly in African genomics research.

The genus Diaphanosoma (Diplostraca: Sididae) in Greece: morphological and molecular assessment

For the genus Diaphanosoma Fischer (Cladocera) the species’ name “D. brachyurum” has been widely used for many decades to identify other species belonging to this genus. To clarify the diversity of the genus in Greek lakes in the present study, we morphologically and genetically identified the Diaphanosoma species occurring in eight lakes. Three hundred twenty-nine Diaphanosoma individuals were morphologically examined, while for the genetic analyses the mtDNA COI gene was sequenced in 48 individuals. Combining the morphological and genetic results, we verified the occurrence of D. mongolianum, D. orghidani and D. macedonicum in our study area. We could not confirm prior records of D. brachyurum and D. lacustris while we provide the molecular identity of D. macedonicum. Furthermore, we highlight the need to check whether the European D. mongolianum populations are characterised of mitochondrial discordance and hybridization as the individuals from the Asian type locality of the species. Our results support the importance of combining both approaches to correctly identify taxonomic species, despite the extra effort and cost during the sample analysis.

Evaluating a communication aid for return of genetic results in families with hypertrophic cardiomyopathy: A randomized controlled trial

Introduction: Genetic testing for hypertrophic cardiomyopathy (HCM) is considered a key aspect of management. Communication of genetic test results to the proband and their family members, can be a barrier to effective uptake. We hypothesized that a communication aid would facilitate effective communication, and sought to evaluate knowledge and communication of HCM risk to at-risk relatives. Methods: This was a prospective randomized controlled trial. Consecutive HCM patients attending a specialized clinic, who agreed to participate, were randomized to the intervention or current clinical practice. The intervention consisted of a genetic counselor-led appointment, separate to their clinical cardiology review, and guided by a communication booklet which could be written in and taken home. Current clinical practice was defined as the return of the genetic result by a genetic counselor and cardiologist, often as part of a clinical cardiology review. The primary outcome was the ability and confidence of the individual to communicate genetic results to at-risk relatives. Results: The a priori outcome of improved communication amongst HCM families did not show statistically significant differences between the control and intervention group, though the majority of probands in the intervention group achieved fair communication (n=13/22) and had higher genetic knowledge scores than those in the control group (7 +/- 3 versus 6 +/- 3). A total of 29% of at-risk relatives were not informed of a genetic result in their family. Conclusion: Communication amongst HCM families remains challenging, with nearly a third of at-risk relatives not informed of a genetic result. We show a significant gap in the current approach to supporting family communication about genetics.

Taming active transposons at Drosophila telomeres: The interconnection between HipHop’s roles in capping and transcriptional silencing

Drosophila chromosomes are elongated by retrotransposon attachment, a process poorly understood. Here we characterized a mutation affecting the HipHop telomere-capping protein. In mutant ovaries and the embryos that they produce, telomere retrotransposons are activated and transposon RNP accumulates. Genetic results are consistent with that this hiphop mutation weakens the efficacy of HP1-mediated silencing while leaving piRNA-based mechanisms largely intact. Remarkably, mutant females display normal fecundity suggesting that telomere de-silencing is compatible with germline development. Moreover, unlike prior mutants with overactive telomeres, the hiphop stock does not over-accumulate transposons for hundreds of generations. This is likely due to the loss of HipHop’s abilities both to silence transcription and to recruit transposons to telomeres in the mutant. Furthermore, embryos produced by mutant mothers experience a checkpoint activation, and a further loss of maternal HipHop leads to end-to-end fusion and embryonic arrest. Telomeric retroelements fulfill an essential function yet maintain a potentially conflicting relationship with their Drosophila host. Our study thus showcases a possible intermediate in this arm race in which the host is adapting to over-activated transposons while maintaining genome stability. Our results suggest that the collapse of such a relationship might only occur when the selfish element acquires the ability to target non-telomeric regions of the genome. HipHop is likely part of this machinery restricting the elements to the gene-poor region of telomeres. Lastly, our hiphop mutation behaves as a recessive suppressor of PEV that is mediated by centric heterochromatin, suggesting its broader effect on chromatin not limited to telomeres.

PATH-22. GENETIC VARIATION BETWEEN IDH MUTANT AND IDH WILD-TYPE GLIOMA

OBJECTIVE The prognosis of IDH mutant glioma was significantly different from that of IDH wild-type glioma. In order to explore the differences between them at the genetic level, we analyzed the genetic results of IDH mutant and IDH wild-type glioma. METHODS This study analyzed the clinical data and genetic results of 45 glioma patients from Jan. 2017 to Dec. 2019, exploring relevant prognostic indicators and the difference in genetic profile between IDH mutant glioma and IDH wild-type glioma. RESULTS 45 patients were included in this study, including 15 IDH mutant glioma patients and 30 IDH wild-type glioma patients. Genetic analysis showed that there was no difference in tumor mutation burden (TMB) and microsatellite instability (MSI) between IDH mutant glioma and IDH wild-type glioma. But somatic mutation between IDH mutant and IDH wild-type glioma was different. The expressions of IDH1, CIC, SYNE1 and TP53 were different in the two groups, among which IDH1 and CIC were more significantly different. Copy number variations (CNV) was also different between IDH mutant glioma and IDH wild-type glioma. STIL occured more frequently in IDH wild-type gliomas. Genetic analysis also showed the difference in variant allel frequence (VAF). IDH mutant gliomas were more likely to be combined with ATRX and TP53 mutations, while IDH wild-type gliomas, in addition to the combination of TP53 mutations, often also combined with the mutations of NF1, BRAF and PTEN. In survival analysis, glioma with IDH mutation has a good prognosis, and IDH wild-type patients have a poor prognosis. In IDH wild-type patients, patients with PTEN mutation have a worse prognosis. CONCLUSION There is an obvious genetic difference between IDH mutation and IDH wild-type glioma, and PTEN mutation is a poor prognostic factor for IDH wild-type patients.

Participants’ Preferences and Reasons for Wanting Feedback of Individual Genetic Research Results From an HIV-TB Genomic Study: A Case Study From Botswana

The feedback of individual results of genomics research is an ethical issue. However, which genetic results African participants would like to receive and why, remains unclear. A qualitative study was conducted to collect data from 44 adolescents and 49 parents/caregivers of adolescents enrolled in a genomic study in Botswana. Almost all the participants wanted to receive genetic results. Parents and caregivers wanted to receive results across all categories of genetic conditions discussed in the study, while adolescents were reluctant to receive results for severe, non-preventable, and unactionable conditions. Participants expressed different reasons for wanting feedback of results, including for awareness, improving lifestyle, accepting one’ situation, and preparing for the future. Our findings also reveal that participants’ context, relations, and empowerment are important to consider in interpreting their preferences for feedback of results.

Case Report: A Deletion Variant in the DCAF17 Gene Underlying Woodhouse-Sakati Syndrome in a Chinese Consanguineous Family

Woodhouse-Sakati syndrome (WSS, MIM 241080) is a rare neuroendocrine disease characterized by hair loss, hypogonadism, diabetes, hearing loss, and extrapyramidal syndrome, and is usually caused by mutations in the DCAF17 gene as an inherited disease. DCAF17 plays an important role in mammalian gonadal development and infertility. So far, there have been no WSS reports in China. The patient introduced in this case is from a consanguineous family. The main symptoms of the patient were alopecia and gonadal agenesis. Other symptoms such as hearing loss, intellectual disability, and hyperglycemia were remarkable, and these symptoms are often observed in WSS patients. We found a nonsense mutation in the 11th exon of the gene DCAF17 (Refseq: NM_025000) in the patient and her younger brother, which confirmed the diagnosis of WSS. The genetic results also showed that the mutation was inherited from their healthy first-cousin parents.

Paleolimnological evidence reveals climate-related preeminence of cyanobacteria in a temperate meromictic lake

Meromictic lakes provide a physically stable environment in which proxies for potentially harmful cyanobacteria are exceptionally well-preserved in the sediments. In Sunfish Lake, a meromictic lake that has recently become the focus of citizen concern due to the apparent rise in cyanobacteria blooms, we used a multi-proxy paleolimnological approach pairing novel spectral (i.e., VNIRS) and molecular (i.e., qPCR) assessment tools to explore long-term cyanobacteria trends. We hypothesized that climate change over the past 50 years altered the Sunfish Lake environment to favour cyanobacteria dominance, resulting in an increased incidence of bloom events. Spectral and genetic results aligned to reveal an unprecedented abundance of cyanobacteria in modern times and coincided with warmer and wetter climatic conditions in the region. Our findings offer evidence for climate-driven shifts in cyanobacteria abundance and suggest that a shift towards warmer and wetter conditions supports the rise of cyanobacteria in lakes.

Can expelled cells/debris from a developing embryo be used for PGT?

Background Preimplantation genetic testing (PGT) is offered to a wide range of structural and numerical chromosomal imbalances, with PGT- polymerase chain reaction (PCR), as the method of choice for amplifying the small DNA content achieved from the blastomere biopsy or trophectoderm (TE) biopsy, that might have a detrimental impact on embryonic implantation potential. Since human embryos cultured until Day-5–6 were noticed to expel cell debris/ fragments within the zona pellucida, we aimed to examine whether these cell debris/ fragments might be used for PGT, as an alternative to embryo biopsy. Methods Blastocysts, which their Day-3 blastomere biopsy revealed an affected embryo with single-gene defect, and following hatching leaved cell debris/fragments within the zona pellucida were analyzed. Each blastocyst and its corresponding cell debris/fragments were separated and underwent the same molecular analysis, based on multiplex PCR programs designed for haplotyping using informative microsatellites markers. The main outcome measure was the intra-embryo congruity of Day-3 blastomere biopsy and its corresponding blastocyst and cell debris/fragments. Results Fourteen affected embryos from 9 women were included. Only 8/14 (57.2%) of embryos demonstrated congruent molecular genetic results between Day-3 embryo and its corresponding blastocyst and cell debris/fragments. In additional 6/14 (42.8%) embryos, molecular results of the Day-3 embryos and their corresponding blastocysts were congruent, while the cell debris/fragments yielded no molecular diagnoses (incomplete diagnoses). Conclusions It might be therefore concluded, that in PGT cycles, examining the cell debris/fragments on Day-4, instead of Day-3 blastomere or Day-5 TE biopsies, is feasible and might avoid embryo biopsy with its consequent detrimental effect on embryos’ implantation potential. Whenever the latter results in incomplete diagnosis, TE biopsy should be carried out on Day-5 for final genetic results. Further large well-designed studies are required to validate the aforementioned PGT platform.