The Genotype and Phenotypes in Families (GPF) platform manages the large and complex data at SFARI.

The exploration of genotypic variants impacting phenotypes is a cornerstone in genetics research. The emergence of vast collections containing deeply genotyped and phenotyped families has made it possible to pursue the search for variants associated with complex diseases. However, managing these large-scale datasets requires specialized computational tools tailored to organize and analyze the extensive data. GPF (Genotypes and Phenotypes in Families) is an open-source platform ( https://github.com/iossifovlab/gpf ) that manages genotypes and phenotypes derived from collections of families. The GPF interface allows interactive exploration of genetic variants, enrichment analysis for de novo mutations, and phenotype/genotype association tools. In addition, GPF allows researchers to share their data securely with the broader scientific community. GPF is used to disseminate two large-scale family collection datasets (SSC, SPARK) for the study of autism funded by the SFARI foundation. However, GPF is versatile and can manage genotypic data from other small or large family collections. Our GPF-SFARI GPF instance ( https://gpf.sfari.org/ ) provides protected access to comprehensive genotypic and phenotypic data for the SSC and SPARK. In addition, GPF-SFARI provides public access to an extensive collection of de novo mutations identified in individuals with autism and related disorders and to gene-level statistics of the protected datasets characterizing the genes' roles in autism. Here, we highlight the primary features of GPF within the context of GPF-SFARI.

Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes.

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10-6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

Effect of the COVID-19 induced phase of massive telehealth uptake on end-user satisfaction.

BACKGROUND: COVID-19 has resulted in a massive increase in telehealth utilisation. AIMS: To determine the user and clinician satisfaction during this period and compare to a pre-COVID-19 cohort. METHODS: A prospectively collected voluntary questionnaire following the telehealth appointment at a tertiary-level hospital with all adult and paediatric-based specialities was conducted over two time periods: COVID-19 (16 March 2020 to 15 April 2020) and pre-COVID-19 (1 January 2019 to 31 December 2019). There were four groups of participants: patients; parents; adult-based clinicians; and paediatric-based clinicians. The outcomes assessed included perceived standard of care, willingness for repeat telehealth consultations, and patient and parental perceptions of safety. RESULTS: Five thousand and thirty-three telehealth consultations occurred in the COVID-19 period with 1757 questionnaires completed, compared to 1917 consultations with 271 questionnaires completed in the pre-COVID-19 period. Clinicians were more likely to have previously used telehealth in both time periods than end-users. In COVID-19, 1240 actual onsite hospital outpatients' visits were prevented. All groups reported a good overall impression of the telehealth quality; patients/parents scored higher compared to clinicians: 3.6/4 versus 3.3/4, P = 0.02 (pre-COVID-19) and 3.3/4 versus 2.8/4, P = 0.001 (COVID-19). The majority of patients and parents (90%, 1379/1528) felt safer by having a telehealth appointment compared to a face-to-face appointment in the COVID-19 pandemic. All participant groups reported an overall good standard of care, good levels of engagement and were strongly willing to use telehealth again in both of the study time periods. Patients and parents consistently rated higher than clinicians. CONCLUSIONS: During a rapid increase in its utilisation and scope due to the COVID-19 pandemic, telehealth was generally well accepted by patients, parents and clinicians, which was consistent with pre-COVID-19 experiences.

Epigenetics in vascular disease - therapeutic potential of new agents.

Vascular diseases, including atherosclerosis, angioplasty-induced restenosis, vessel graft arteriosclerosis and hypertension-related stenosis, remain the most prevalent cause of death in the developed world. The aetiology of vascular diseases is multifactorial with both genetic and environmental factors. Recently, some of the most promising research identifies the epigenetic modification of the genome to play a major role in the disease development, linking the environmental insults with gene regulation. In this process, modification of DNA by methylation, and histone modification by acetylation, methylation, phosphorylation and/or SUMOylation are reported. Importantly, recent studies demonstrated that histone deacetylase (HDAC) enzymes are crucial in endothelial integrity, smooth muscle proliferation and in the formation of arteriosclerosis in animal models. The study of HDACs has shown remarkable specificity of HDAC family members in vascular cell growth/death that influences the disease process. Interestingly, the effects of HDACs on arteriosclerosis development in animal models have been observed after HDAC inhibition using specific inhibitors. This provides a new approach for the treatment of vascular disease using the agents that influence the epigenetic process in vascular cells. This review updates the rapid advances in epigenetics of vascular diseases focusing on the role of HDAC family in atherosclerosis. It will also discuss the underlying mechanisms of histone acetylation in vascular cells and highlight the therapeutic potential of such agents.