What Have We Learned from Patients Who Have Arboleda-Tham Syndrome Due to a De Novo KAT6A Pathogenic Variant with Impaired Histone Acetyltransferase Function? A Precise Clinical Description May Be Critical for Genetic Testing Approach and Final Diagnosis.

Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268). The analysis revealed the presence of de novo pathogenic variant in KAT6A gene, a nucleotide c.3385C>T substitution that introduces a premature termination codon (p.Arg1129*). The need for straight multidisciplinary collaboration and accurate clinical description findings (bowel obstruction/megacolon/intestinal malrotation) was emphasized, together with the utility of CES in establishing an etiological basis in clinical and genetical heterogeneous conditions. Therefore, considering the phenotypic characteristics, the condition's rarity and the reviewed literature, we propose additional diagnostic criteria that could help in the development of future clinical diagnostic guidelines. This was possible thanks to objective examinations performed during the long follow-up period, which permitted scrupulous registration of phenotypic changes over time to further assess this rare disorder. Finally, given that different genetic syndromes are associated with distinct genomic DNA methylation patterns used for diagnostic testing and/or as biomarker of disease, a specific episignature for ARTHS has been identified.

An in silico pipeline approach uncovers a potentially intricate network involving spike SARS-CoV-2 RNA, RNA vaccines, host RNA-binding proteins (RBPs), and host miRNAs at the cellular level.

BACKGROUND: In the last 2 years, we have been fighting against SARS-CoV-2 viral infection, which continues to claim victims all over the world. The entire scientific community has been mobilized in an attempt to stop and eradicate the infection. A well-known feature of RNA viruses is their high mutational rate, particularly in specific gene regions. The SARS-CoV-2 S protein is also affected by these changes, allowing viruses to adapt and spread more easily. The vaccines developed using mRNA coding protein S undoubtedly contributed to the "fight" against the COVID-19 pandemic even though the presence of new variants in the spike protein could result in protein conformational changes, which could affect vaccine immunogenicity and thus vaccine effectiveness. RESULTS: The study presents the findings of an in silico analysis using various bioinformatics tools finding conserved sequences inside SARS-CoV-2 S protein (encoding mRNA) same as in the vaccine RNA sequences that could be targeted by specific host RNA-binding proteins (RBPs). According to the results an interesting scenario emerges involving host RBPs competition and subtraction. The presence of viral RNA in cytoplasm could be a new tool in the virus's armory, allowing it to improve its chances of survival by altering cell gene expression and thus interfering with host cell processes. In silico analysis was used also to evaluate the presence of similar human miRNA sequences within RBPs motifs that can modulate human RNA expression. Increased cytoplasmic availability of exogenous RNA fragments derived from RNA physiological degradation could potentially mimic the effect of host human miRNAs within the cell, causing modulation of the host cell network. CONCLUSIONS: Our in silico analysis could aid in shedding light on the potential effects of exogenous RNA (i.e. viruses and vaccines), thereby improving our understanding of the cellular interactions between virus and host biomolecules. Finally, using the computational approach, it is possible to obtain a safety assessment of RNA-based vaccines as well as indications for use in specific clinical conditions.