The days were divided into the different environments in which genetics plays a role including clinical genetic testing, data, care and counselling, past environments, populations and community and family.  International and local speakers presented their research into the impact of genetics on the environment that they represent. This article provides insight into what these sessions looked like and the research in South Africa and further afield. 

Our genes, our environment was the theme of the 18th biennial congress of the Southern African Society for Human Genetics.

Prof Maritha Kotze, Division of Chemical Pathology, Stellenbosch University and the National Health Laboratory Service (NHLS) reports on: 

Our genes in the clinical genetic testing environment

Genetic testing in the clinical setting is used to identify the underlying genetic cause of a disease.  In Mendelian inherited disorders this is due to a pathogenic variant in a disease-causing gene.  Due to many genes being associated with a clinical picture it is beneficial to study all at the same time to identify the one that may be involved.  That said, sometimes the gene associated with a condition is not known, then it is beneficial to look further and perform whole genome testing.

The genomics landscape has changed from searching for specific variants in parts of a gene to massively parallel panel (multiple genes studied or sequenced at the same time)/genome sequencing, coupled with robotics that can handle large numbers of samples at a time, and software to capture the full spectrum of genetic variation.

But application of personalised medicine as the purpose of genomic testing in a clinical context faces numerous challenges, according to keynote speaker, gastroenterologist and medical geneticist from the United States, Prof Robert Nussbaum. These include high costs, long turn-around time, complex patient and genetic test guidelines, lack of data sharing and consensus around clinical utility.

Non-specialist service providers are therefore uncomfortable requesting testing for patients. However, said Prof Nussbaum, genetic testing is no longer limited by cost.

In addition, guidelines for the interpretation of sequence variants were published by Richards et al in 2015. Criteria used includes population data, variant type, functional data, de novo mutational events and data about other alleles reported in databases.

Different laboratories sometimes report contradictory information on the same variant. Standardisation of delivery of results focused on Mendelian inheritance acknowledges that there is not always consensus on the meaning of a specific variant. It is not only the code in the DNA nucleus that counts, but also interaction with the environment and microbiome.

The functional effect of a variant is only one line of evidence and is not equal to the pathogenesis eg causal pathways underlying the disease in a particular patient. Old literature sources are full of errors, with 5%-10% revealed to be false when open access databases such as ClinVar, Exac and gNOMAD became available.

Making sense of mutations that change the protein make-up (missense) remains a problem.  New technology tackling these issues include saturation genome editing and other technologies such as single cell profiling providing pathogenicity scores. These developments require re-evaluation of gene variants on an annual basis to identify cases where a new interpretation implies a change in personal / clinical utility.

Since people move and may change doctors, recontact of patients to issue a report update is considered a shared responsibility. The laboratory is responsible for providing this information to the treating clinician with the knowledge of the patient.

Analysis of pathogenic variants for cancer-associated genes

Yasmina Jaufeerally-Fakim of the Biotechnology Department at the University of Mauritius presented a paper on pathogenic variants in cancer-associated genes in selected African populations. The high incidence of breast, prostate and some other forms of cancer in Africa is alarming, given the fact that only 20 African countries have cancer registries. Significant differences in mutation spectrum were reported between different African populations, with a noticeable effort to return actionable whole exome sequencing results to breast cancer patients in Kenya. This experience contributed to the development of a tiered informed consent form for return of research results in resource-limited African settings.

Emma Frickel, MSc candidate, Stellenbosch University reports on: 

Our genes and past environments

From the study of complex traits to medical genetics and forensic applications, this session highlighted the importance of considering and understanding the history of man – where we come from. In essence, our history is reflected in our genes.

The session commenced with a keynote address by Dr Chris Gignoux of the Colorado Center for Personalized Medicine (United States). The underrepresentation of diverse populations, along with how genetic diversity contributes to our understanding of complex traits and clinically relevant variants, considered one of the shortcomings in large-scale genomic studies, have been addressed.

Along with massive collaborative efforts and global consortia, the sheer number of individuals included in these studies naturally presents more genetic diversity than in study designs involving small homogeneous cohorts.

In the context of medical genomics, homogeneity is essential and it is important to consider demographic history. When comparing pathogenic and benign variants, it is often observed that pathogenic variants are extremely rare and tend to be population specific.

It was shown that factoring in fine-scale population structure reveals trends in population-specific variant frequencies that would otherwise be overlooked when grouping these populations together.

This topic is especially applicable in an African context.  Africa is home to the most genetically diverse populations in the world. This untapped genetic resource warrants understanding and provides new opportunities for biomedical discoveries, identifying populations that may be at elevated risk, and avoiding ancestry-related misdiagnoses that have happened in the past.

The importance of our demographic history was again highlighted in subsequent presentations, two of which involved research that falls within the Africa Wits-INDEPTH partnership for Genomic Studies.

The first of these studies revealed sex-specific inbreeding depression patterns of certain anthropometric and lipid composition traits, which suggested a dominant genetic architecture for some of these complex traits in the sub-Saharan study population. Sex-specific inbreeding depression is considered one of the driving forces for the evolution of reproductive morphology, physiology, behaviour and mating systems.

The second study revealed novel complex population sub-structure within South Eastern Bantu speaking groups, which mirror the geographic distribution of ethnolinguistic groups within South Africa.

This emphasises the importance of considering geography along with historical migration and ethnolinguistic affiliations for effective genetic association studies in an African context.

The next study looked at migration, admixture and selection patterns in the Indian Ocean trade network and provide insight into the population-specific diversity of the Duffy antigen/chemokine receptor (DARC locus), showing strong adaptive selection that occurred in this region.

The session was concluded with a presentation on Y-chromosome forensics in South Africa, in the context of the UniQ-TyperTM Y-10 that was developed specifically for local populations. The kit can be used for forensic investigations relating to sexual assault analyses and genealogy evaluation and can also be used to infer geographic occurrence of certain genetic variation profiles.

Considering the research presented in this session, the past should not always remain in the past, as it is intrinsically linked to our current genetic architecture and is thus relevant for current and future genomic research.

Maxine du Toit, genetic counselling intern, University of Cape Town reports on:

Our genes in the community and family environment

As clinical genetic professionals we see the impact of a genetic condition or teratogenic exposure to a foetus stretch far beyond the affected person to social and emotional impact on the family and their community. This highlights the importance of acknowledging the social impact of a condition and not just the genetics and providing support where possible and appropriate.

Keynote speakers, emeritus Prof Hein Odendaal of the Department of Obstetrics and Gynaecology at Stellenbosch University, and colleague, Prof Michael Urban of the Division of Molecular Biology and Human Genetics, spoke about the effect of teratogenic exposure during pregnancy.

Prof Odendaal presented his research paper entitled The prenatal environment: Exposure to teratogens in a Cape Town cohort and emphasised the compounding risk for stillbirth and sudden infant death syndrome in offsprings of mothers who drink and smoke during pregnancy. Prof Urban’s presentation focussed on how smoking modifies the effect of alcohol on facial features of children with foetal alcohol syndrome.

Dr Helen Malherbe, Chair: Governing Board, Genetic Alliance South Africa, presented her modelled data on oral facial clefts based on available data from the National Department of Health and algorithms used for epidemiological studies.

Kelly du Plessis presented on genetic disease within the context of genetic support groups. As CEO and founder of Rare Diseases South Africa, Kelly shared information about the link between support groups, researchers and healthcare providers within the context of modern-day patients with easy access to information via social media.

The traditional role of the healthcare provider as sole information-holder is something of the past, and Kelly presented a practical model on how modern-day patients together with research, clinicians, palliative care and support groups come together to collaborate to advance medical care.

Our genes in the care and counselling environment

The topics presented during this session personified the underlying reason for scientific and technological advancement in the genomics era: The human ‘behind’ the genes. It amplified that all the scientific excellence and progress is ultimately for the use of the patient. The session illustrated how genetics enter the clinical environment as well as the lives of individuals.

Keynote speaker Prof Jehannine Austin, a genetic counsellor and Canada Research Chair in Translational Psychiatric Genomics, shared some of her expertise in practicing genetic counselling in the context of psychiatric disorders. She found that understanding the cause of illness is profoundly important to families and can result in meaningful positive outcomes by lifting the burden of guilt and fear and helping people to adapt positively to their diagnosis.

Prof Nussbaum presented his research on the aetiology of Parkinson’s disease – work for which he has won numerous awards. He discussed various genes associated with the development of the disease and as well as their presentation in families.

Genetic counsellor, Dr Chantelle Scott spoke about decision-making with regard to Down syndrome prenatal testing, and termination of pregnancy in a South African setting. She presented a multi-faceted mind-map explaining how various factors influence the way that such decisions are made.

Emeritus prof Arnold Christianson shared some of his experience as a geneticist specialising in cerebral palsy medico-legal matters in South Africa. Many parents of children with cerebral palsy claim negligence by healthcare professionals and geneticists are tasked with ruling out causative genetic risk factors in lawsuits. Prof Christianson found that in 25.8% of 124 cases referred to him, there were underlying genetic risk factors and he cautioned geneticists to expect more such medico-legal cases as referrals in the future.

Dr Liani Smit, a registrar in clinical genetics at Stellenbosch University, presented an interesting South African case series on lethal multiple pterygium syndrome, a fatal condition on the severe end of the foetal akinesia spectrum.

Dr Heidré Bezuidenhout, medical geneticist at Stellenbosch University shared some of her experiences using artificial intelligence to diagnose rare genetic conditions. Although the clinical utility of computer-based systems such as Possum and Face2Gene are sometimes questioned, it helped her diagnose a patient with Mabry syndrome – a four-year long diagnostic odyssey. On multiple occasions the programme Face2Gene has been a useful diagnostic option and is worth investigating.

Monica Araujo, genetic counselling intern at the NHLS and the University of the Witwatersrand, presented her Masters degree research, performed at the University of Cape Town, on the perspectives and experiences of individuals undergoing predictive testing for hereditary breast and ovarian cancer syndromes in the Western Cape. She concluded that additional emotional support through predictive testing is needed. Clair Engelbrecht, genetic counsellor at Stellenbosch University presented on the comparison of two testing strategies of these syndromes at Tygerberg hospital (Western Cape).

Dr Shelley Macaulay, genetic counselling manager and genetic counsellor at the NHLS and the University of the Witwatersrand presented her research on the reliability and validity of reported last menstrual period timing to estimate gestational age in a low-to-middle-income setting. Dr Candice Feben, medical geneticist at the NHLS and the University of the Witwatersrand spoke about endocrine profiling in Black South African Fanconi anaemia patients homozygous for a Fanconi anaemia group G protein founder mutation. Bianca Carzis, genetic counsellor at the NHLS and the University of the Witwatersrand, concluded the session by sharing a patient’s journey to parenthood titled: It was preimplantation genetic diagnosis or no kids.

Natasha Kitchin, Department of Psychiatry Research, Stellenbosch University reports on: 

Our genes in the data environment

Next-generation sequencing (NGS) has generated large volumes of data which has led to scientific breakthroughs but has also resulted in researchers struggling to keep up with the masses of data.

This session highlighted ways in which researchers are tackling this issue. With an increase in demand for breast cancer gene testing came the implementation and validation of NGS to increase capacity and decrease processing time and cost. Similarly, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a custom genotyping array optimised for identifying genetic associations with prostate cancer in African populations.

This array includes 1.5 million markers as well as ancestry informative markers, which will allow investigators to identify novel African-based disease associations and to fine-map genetic loci that are associated with prostate cancer.

Every cell in our body has the same genetic information. The cell variety in our body is as a result of differential gene expression, a topic tackled by our first presenter who delved into RNA sequencing, in this case single-cell RNA sequencing, which allows for the investigation of gene expression in a single cell type using the Smart-Seq2 protocol. Following on from this, one of the presenters developed robust and reproducible bioinformatic pipelines for the automation of RNA sequencing data analyses – rnaSeqCount for mapping RNA sequencing reads to a reference genome for differential gene expression analyses, and rnaSeqMetagen for performing metagenomic analyses using RNA sequencing data.

In today’s big data powered world, being a genetic researcher means figuring out a way to analyses big data in genetics. Using SNP-based heritability estimates, a recent study found that childhood trauma was estimated to be approximately 5% heritable. This study also found that childhood trauma was significantly correlated with depressive symptoms.

Following on from this, one of the presenters used an integrative approach to investigate the effects of genetics, neuroanatomical variation, and childhood trauma, and found a positive correlation between brain region volume and schizophrenia treatment response.

Machine learning is a method of data analysis that automates analytical model building. These systems learn from data, identify patterns and generate predictable outcomes. Machine learning was implemented in a study on the effect of alcohol on the gut microbiome of pregnant women, which found that levels of the bacteria.

Prevotella was higher in women who consumed alcohol during pregnancy. High levels of Prevotella may result in a compromised intestinal barrier, which, in turn, may result in increased translocation of bacteria across the normally impenetrable intestinal barrier and into the bloodstream.

The first pan-African Genome Wide Association Study for lipid traits such as total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides was reported. Interestingly two variants associated with low-density lipoprotein cholesterol levels were only polymorphic in African populations, reiterating that Africa is home to the most genetically diverse populations in the world.

The session also included keynote addresses from Prof Hugh Patterton and Prof Nicki Tiffin. Prof Patterton of the Centre for Bioinformatics and Computational Biology at Stellenbosch University shared his research on silent information regulator proteins that regulate gene expression.

Prof Tiffin of the Department of Integrated Biomedical Sciences at the University of Cape Town shared her thoughts on how to perform ethical genomic research in Africa with a special focus on the South African Protection of Personal Information Act that will be coming into effect soon.