Introduction
Rare diseases (RDs) affect approximately 6-8% of the population worldwide (Aymé, 2012; Baird et al., 1988). To date, about 6,000 to 7,000 different rare diseases with suspected genetic etiologies have been described (Sawyer et al., 2016) and in almost 4,500 of them the causative gene(s) have been identified (OMIM April 2020 updated, Amberger et al., 2019). The advent of Next-Generation Sequencing (NGS) technologies has revolutionized genomic research and diagnostics, representing a major advance in the identification of pathogenic genetic variations (Baynam et al., 2016; Hartman et al., 2019; Lim et al., 2015; Rabbani et al., 2012; Smith et al., 2019; J. Taylor et al., 2019).
Whole Exome Sequencing (WES) involves the analysis of protein-coding regions of the total human genome (representing <2%), which is currently believed to include the majority of causative variants in monogenic diseases (Adams & Eng, 2018). WES application for clinical diagnostics has completely changed the landscape of medical genetics. Compared to conventional testing strategies, WES facilitates a faster and more cost-effective route for definite diagnosis of rare genetic diseases, minimizing previous “diagnostic odysseys” experienced by many patients and their families (Bertier et al., 2016; Iglesias et al., 2014; Niguidula et al., 2018; Yang et al., 2013). Several studies have showcased a high WES diagnostic rate, ranging from 25% to 40%, (Jalkh et al., 2019; Reuter et al., 2019; Sawyer et al., 2016; Seaby et al., 2016; Valencia et al., 2015). This is likely influenced by a variety of factors including the strategy of analysis (proband alone versus trio of proband and parents), family history, type of disorder, age of onset, and acuity of the clinical evaluation (Taylor et al., 2015). Correct interpretation of WES data presents a challenge, entailing filtration and classification of ~30.000 variants distributed across the coding genome of every case.
When it comes to genetic services, the diagnostic yield and clinical utility of WES are highly dependent on the close collaboration of a multidisciplinary team, including clinical geneticists (or referring clinicians) and laboratory geneticists. In our experience, definitive diagnosis was reached in more than half of the patients referred for WES, highlighting the importance of applying stringent testing and bioinformatic protocols, complimented by a robust phenotypic-driven strategy for variant evaluation.