Proceedings of the 25th Annual Meeting of the Portuguese Society of Human Genetics (SPGH – Sociedade Portuguesa de Genética Humana)

Porto, 18-19 November 2021Letter from the SPGH President The 25th Annual Meeting of the Portuguese Society of Human Genetics (SPGH – Sociedade Portuguesa de Genética Humana) took place on November 18th and 19th, 2021 in virtual format, for the second consecutive year. It represents the largest annual event in the field of Medical and Human Genetics in Portugal, bringing together the national experts in the field, as well as some invited international scientists. This meeting was also an occasion to celebrate the 25th anniversary of the Society. To this purpose, this year’s program included a commemorative session where the beginning of Medical Genetics in the country and the creation of the Society were revisited. The scientific sessions addressed topics such as the advances in knowledge of mechanisms and treatment of genetic diseases, the importance of quality in the provision of genetic care and the challenges that the future brings. We registered the submission of nearly one hundred scientific abstracts for oral or poster communication, hereby published. We would like to thank all the invited speakers and session moderators, that ensured the scientific quality of the sessions. Jorge Pinto Basto SPGH PresidentOral presentations Basic Research OP1 MUTANT ATAXIN-2 PATHOLOGICAL FEATURES IS ALTERED BY THE AGING PROCESS Inês Torquato Afonso1, Patrícia Lima2, Carlos A. Matos1, Clévio Nóbrega1 1Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, Faro, Portugal; Algarve Biomedical Center – Research Institute, Faro, Portugal;2Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, Faro, Portugal Aging is a natural process which can be defined as a time-dependent functional decline of an organism. This process is characterized by different molecular hallmarks, including oxidative stress, epigenetic alterations, loss of proteostasis, dysregulated nutrient-sensing (1). Some genetic disorders like Spinocerebellar Ataxia type 2 (SCA2) occur later in life and are associated with neurodegeneration of specific brain regions (2). SCA2 is an autosomal dominant disorder where the product of the mutant gene ATAXIN-2, originates a mutant protein with propensity to aggregate which seems to be toxic for neurons. This project aims to investigate the impact of aging upon in the neuropathological features related with mutant ataxin-2 expression. Briefly, 3 and 18-months-old C57BL/6 mice were injected in the right hemisphere of the striatum with lentiviral vectors encoding for the human mutant ATAXIN-2 gene, while the contralateral hemisphere was injected with wild-type ATAXIN-2, as control. Twelve weeks post-injection the animals were sacrificed, and brain tissue was analyzed. The 18-month-old animal group injected with mutant ATAXIN-2 had significantly increased number of pathological aggregates, as well as higher volume of neuronal loss in comparison with the 3 months old animals. Other aging hallmarks, such as inflammation, epigenetic, mitochondrial, and apoptotic markers were evaluated in this project. The results indicate that mutant ATAXIN-2 expression has more prominent effect in old animals, supporting an impact of aging in the neuropathological abnormalities caused by mutant ATAXIN-2 expression. References 1. López-Otín C,et al. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217. 2. Seidel, K., et al. Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 2012 124, 1–21. Acknowledgment This study was funded by the Portuguese Science and Technology Foundation (FCT) project (ALG-01-0145-FEDER-29480) “SeGrPolyQ”, with CRESC ALGARVE 2020 cofunding, the French Muscular Dystrophy Association (AFM-Téléthon) project #22424 and by the Ataxia UK (ZUNIALGA project). OP2 THE CDH1 LOCUS REGULATORY ARCHITECTURE: CDH1 NONCODING ELEMENTS CONTROL E-CADHERIN CANONICAL FUNCTIONS São José C.1, Barbosa-Matos R.2, André A.3, Ferreira M.4, Lobo S.2, Pinheiro H.3, Mundlos S.5, Huntsman D.6, Oliveira C.7 1i3S/Ipatimup, Porto, Portugal; FMUP, Porto, Portugal; MPIMG, Berlin, Germany;2i3S/Ipatimup, Porto, Portugal; ICBAS, Porto, Portugal;3i3S/Ipatimup, Porto, Portugal;4i3S/Ipatimup, Porto, Portugal; FCUP, Porto, Portugal;5MPIMG, Berlin, Germany; IMHG, Berlin, Germany; BCRT, Berlin, Germany;6UBC, Vancouver, British Columbia, Canada; CTAG, Vancouver, British Columbia, Canada; UBCVGH, Vancouver, British Columbia, Canada;7i3S/Ipatimup, Porto, Portugal; FMUP, Porto, Portugal Introduction: E-cadherin is a cell-cell adhesion molecule involved in homeostasis, mobility, polarity, proliferation and differentiation. Loss of expression of E-cadherin is classically associated with epithelial tumour progression and is one of the epithelial to mesenchymal transition (EMT) hallmarks. Herein, we wish to disclose the contribution of the noncoding portion of CDH1 to the canonical functions attributed to this molecule. Materials and Methods: We performed a bioinformatics analysis based on open chromatin and chromatin-interaction profiles and prioritized two CDH1 intronic Cis-Regulatory Elements (iCREs) for CRISPR-Cas9 editing in two gastric cancer cell lines. RNA-seq, ATAC-seq, and 4C-seq with a viewpoint in the CDH1 promoter, were performed in parental cell lines and iCREs CRISPR-Cas9 edited clones. Results: 4C-seq revealed CDH1 promoter interactions with the two selected iCREs. RNA-seq and pathway analysis showed that deletion and/or inversion of CDH1 iCREs impaired most E-cadherin canonical functions. Edited clones with E-cadherin loss of expression presented genome-wide closed chromatin at CpG islands, promoters, TSS and introns, as opposed to clones retaining normal E-cadherin expression. Chromatin accessibility was directly correlated with differential RNA expression profiles. Specifically, pathways associated with E-cadherin impairment, such as adhesion, migration, cadherin binding and EMT were deregulated in both the transcriptome and chromatin accessibility. This effect was even stronger if both iCREs were simultaneously disrupted. Conclusion: We disclosed a chromatin-regulatory network involving two CDH1 intronic regulatory elements that interact with the CDH1 promotor, profoundly affect the genome-wide chromatin accessibility and expression of adhesion, migration and EMT-associated molecules, and globally control fundamental functions attributed to E-cadherin. Funding: 1) Solve-RD project, grant agreement No 779257 (European Union’s Horizon 2020 research and innovation programme); 2) FEDER/COMPETE, “P PTDC/BTM-TEC/30164/2017”, “PTDC/BTM-TEC/6706/2020”, “22184”; 3) FCT Fellowship, “SFRH/BD/140796/2018”. OP3 TRANSCRIPTOMIC CHARACTERIZATION OF HUMAN IPSC-DERIVED CARDIOMYOCYTES Beatriz Gomes-Silva, Marta Ribeiro1, Marta Furtado1, Sandra Martins1, Teresa Carvalho1, Pedro Barbosa1, Rosina Savisaar1, Maria Carmo-Fonseca1 1Instituto de Medicina Molecular Introduction: Cardiomyocytes derived from human iPSCs (iPSC-CMs) are rapidly becoming a promising model to study the pathogenesis of genetic heart diseases and to develop new therapies. Nonetheless, in order to use iPSC-CMs as a disease model, it is important to characterize the extent to which they are able to recapitulate the biological processes of a real heart. Methodology: We performed a transcriptomic characterization of iPSC-CMs derived from healthy patients using single-cell RNA-seq and bulk RNA-seq data. The results were compared with publicly available datasets of human hearts, both adult and fetal. Results: Based on single-cell sequencing data, we found the majority of cells in iPSC-CM cultures correspond to atrial- and ventricular-like cardiomyocytes. Genes that are significantly upregulated in hearts over iPSC-CMs are enriched for angiogenesis and immunity-related pathways, revealing expected biological differences between in vitro cell cultures enriched for cardiomyocytes, and a complex tissue containing cells other cardiomyocytes. it we found an in and pathways, to is between and adult hearts, and in with the of in heart and are or between iPSC-CMs and hearts, with the iPSC-CMs for both gene expression and of the found in were also and adult some as related were results that the transcriptome of human iPSC-CMs the gene expression and in the human heart. We between and adult hearts, the of in heart by the Marta São Porto, Porto, Porto, Portugal; Porto, Porto, Porto, Porto, Porto, Porto, Porto, Portugal; Berlin, Porto, Porto, Portugal Introduction: are to such as or which that of the that analysis in regions of analysis is to and is as the for that of analysis and are the to use of Herein, we a analysis to mechanisms in Methodology: from were to quality and and were to was for the analysis of to the of Results: The of in all was on with on of and while The analysis prioritized by at two that we as intronic by 3 and two were by 2 and and affect a of a gene that the in and all also the is in the for Herein, we a analysis that in with to be This the of a for analysis that is and in Research OP1 José de de de of Medical Genetics and of of and Molecular Genetics and of Human Medical of of Human for Molecular The of and of British Columbia, Vancouver, the in diseases project of Medical Genetics and for Research Biomedical Research of including number in cancer genetic tumour can be and to and/or that and and be found for all for is in We that in some of the The project, from gastric cancer and cancer were with different from were prioritized for in quality and by and/or were evaluated using and 3 were found in in with an CDH1 by is found in by it was an deletion in was by an the of the and the beginning of the gene was found and by by a different for in directly associated with a deletion in associated with was also by this a in at of OP2 of and of and Molecular of of and of and Molecular of of for and Biomedical Research and Center of of for and Biomedical Research and Center of on Genetics and of of of and Medical Introduction: and cell in the of the by the of number and that to genetic expression. 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Pedro – de e Universidade do Porto, – de Universidade do Porto, Portugal, – de Ciências Universidade do Porto, of Universidade de Portugal; de de e – e of of Technology – de e Universidade do Porto, Portugal; – of Molecular and of the of Porto, Portugal; of of of Porto, – de e Universidade do Porto, Portugal Introduction: The has a in human disease and treatment is associated with and The of of the complex and of the gastric the of new and advances in the of of the of an a we a supporting and and Methodology: based on was to a The was by of of a by The and between of the the a can be to The represents the of the gastric the epithelial the and the The was characterized to the by the and in gastric were Results: The by the epithelial and differentiation. are of the normal gastric are in gastric cell the some functional features of the epithelial and increased Conclusion: The the importance of the effect of in order to recapitulate in features of the The represents an in a as a to study gastric THE OF THE 1Instituto de in such as cell and and homeostasis, has also a tumour protein in and gastric as it is in the and correlated to RNA 1) expression. some like cell cell migration and and the pathway a for gastric we investigate the importance of in in we a with two in which we the second occur We the in vitro and and cells with such with the and The results a in compared to of the both in normal and in the of the and analysis of showed that and of are the for the to we RNA and and a expression. in cells and in cells with and in cells and in cells with This be the of a new cancer by the THE OF OF Inês A. 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