Exploring variant effects to advance precision medicine with Wellcome Connecting Science 

I felt privileged to attend these events, held at the Hinxton Hall Conference Centre, on the Wellcome Genome Campus from 10-14th July 2023. They provided an unparalleled platform to present my research, engage with peers, and collaborate with experts from diverse fields.

The CCG conference focused on the latest advancements and challenges in deep-mutational scanning, and how researchers and clinicians can leverage the expanding genomics data to enhance clinical decision-making and advance personalised patient care. The conference commenced with a keynote address by Dr Ambroise Wonkam, from John Hopkins University, USA. Dr Wonkam emphasised the importance of understanding African genomes in identifying disease drug targets, as all modern humans trace their ancestry to Africans; citing the presence of 10% more DNA in the African pan-genome compared to the current human genome. Dr Wonkam concluded his talk with a call for the “3MAG project”, which aims to sequence at least three million African genomes. This resonated strongly with the community; promoting encouragement for equitable, innovative, and sustainable genetic medicine.

The subsequent session explored genetic locus heterogeneity, genetic pleiotrophy, coding and non-coding genome variations, and the development of new methodologies to improve established functional assays and enhance variant classification. Notably, talks by Dr Nadia Carstens, on genomic medicine in Africa, and Dr Elizabeth McNally, on the monogenic and polygenic risk of heart disease, shed light on the importance of exome sequencing for rare developmental disorders and genetic variation of cardiomyopathies. Furthermore, discussions led by Dr Heide Cope emphasised the challenge of integrating genomic findings into clinical practice, and the role of ClinGen in generating guidelines for variant interpretation. Dr Andrew Wilkie provided valuable insights into the pathogenic variants in FGFR1 and FGFR3 genes associated with craniosynostosis. Dr Wilkie also proposed an innovative approach using patient-derived iPSCs, to complement and potentially replace, the resource-intensive mouse models.

The second day of CCG began with a captivating presentation by Dr Segun Fatumo, reiterating the significance of the African Genome and the vast genetic variations present within Africans compared to Eurasians. He highlighted the growing availability of large-scale African genome resources, emphasising their critical role in achieving genetic risk prediction. The subsequent sessions focused on clinical variant classification, and how non-coding regions are equally important for variant classification. Dr Nicky Whiffin emphasised the relevance of non-coding regions, which constitute a substantial portion of the genome, and highlighted the need for epigenetic data, as well as silico tools, to accurately interpret genetic variants. This session was followed by Dr Leslie Biesecker putting forward the recommendations on the interpretation of variants, outlining improvements from past guidelines. His informative talk covered the historical development of variant classification recommendations from 2000 to the most recent version in 2023. Dr Biesecker provided essential insights into defining variant “classification” and “interpretation”, encouraging a standardised approach in the field. Moreover, he addressed the importance of designating changes as “variants” rather than “mutation” or “polymorphisms”.

The final session of CCG focused on the functional assays, where I had the privilege to present our research on Saturation genome editing (SGE) of BRCA2 variants, along with Sofia Obolenski talking about the classification of POT1 variants, and Dr Haico van Attikum discussing PALB2 missense variants, shedding light on their implications in breast cancer susceptibility.

The conclusion of CCG  – with its strong emphasis on functional assays –  provided a seamless transition to the MAVE workshop, which served as a perfect blend of ideas, discussing the utilisation of MAVE data for clinical variant classification. Dr Alan Rubin highlighted the curation of MAVE-DB website, an open access resource that allows sharing variant data from multiple genes obtained through orthogonal assays. This collaboration, and data sharing initiative, foster the advancement of variant classification. Dr Greg Findlay, one of the pioneers of SGE, shared valuable insights into the power and experimental strategies required for successful SGE experiments.

The workshop was the perfect introduction to the Mutational Scanning Symposium (MSS), jointly organised by the WCS Learning and Training team and the Atlas of Variant Effect (AVE) alliance. The keynote address by Dr Fritz Roth described the genotype to phenotype problem, and the impact of environment in this relationship. The power of deep mutational scanning was demonstrated through variant atlas maps for 15-18 proteins with a detailed discussion on HMBS, MTHFR and LDLR genes.