Dear Colleagues,

In the last 10 years, the molecular approach for the study of genetic disorders has completely changed. Molecular diagnosis is based on the identification of the causative variant that allows genetic counseling, prenatal diagnosis, understanding of pathological mechanisms, and, eventually, personalized therapeutic approaches. However, high-throughput DNA analyses (i.e., exome and genome sequencing) have not yet reached a full diagnostic sensitivity, and several patients have no diagnosis in the absence of the identification of the responsible gene/locus. Indeed, the technologies currently used for detecting causal genetic variants lead to many variants of unknown significance (VUSs) and are mainly based on the use of whole-exome sequencing, thus neglecting the identification of non-coding and structural variants. This Special Issue aims to summarize our current abilities in the investigation of the human exome/genome as well as the clinical utility and applicability of the knowledge about coding and non-coding genomic regions. Among the different topics, this Issue intends to cover: (i) the analytical sensitivity of different DNA sequencing technologies (i.e., amplicon-based vs. enrichment-based sequencing, short- vs. long-read sequencing, single-molecule DNA sequencing) for the identification of both single-nucleotide and copy number variants; (ii) methods for investigating the functional roles of synonymous, 5’UTR and 3’UTR variants; (iii) the possibility of establishing a frequency threshold of variants’ allele frequency in different populations, and how referring to a “pan-genome” would increase our power to connect variation to human diversity and disease; and (iv) the current application of multi-omics approaches and how they could improve the diagnostic power of genetic testing.

Dr. Irene Bottillo
Dr. Laura Pezzoli
Guest Editors

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• genomic big data
• DNA sequencing technologies
• molecular genetics
• multi-omics
• variants of unknown significance (VUSs)
• copy number variants (CNVs)
• non-coding variants