# Genomic Approaches for Monogenic Kidney Diseases:
## 2 Genetic Testing: The Current Framework
### Whole-Exome Sequencing  
The WES approach captures the majority of genomic coding regions. It is estimated that up to 85% of all pathogenic mutations fall within this region. WES is mainly applied in cases of unclear clinical suspicion. This technology enables the analysis of targeted genes, whilst maintaining information for future \"virtual panel\" analyses as new genomic components are identified. The employment of a WES based virtual panel reduces the computational burden and restricts the occurrence of incidental findings, while preserving data for reanalysis as additional genetic discoveries emerge [56]. WES exhibits low coverage compared to other methods and often requires Sanger sequencing to increase the depth of analysis [16]. WES does not achieve a complete coverage of the exome in some areas, such as GC-rich regions and homology sequences [66]. The GC content can reduce the efficiency of nucleotide hybridization, causing lower sequencing coverage [67; 68] and requiring modified Polymerase Chain Reaction (PCR) conditions and the design of exon-specific primers. However, the employment of long-read sequencing technology in the WES approach (third-generation sequencing), may overcome the low coverage challenge and enhance sensitivity, especially in high-homology regions [69]. WES technology remains a cost-effective option compared to WGS [70], with simplified data analysis and storage. [PERSON] et al. reported that, compared to kidney biopsy, WES is a lower risk and more cost-effective approach for children with a glomerular disease [31]. Table 1 highlights the heterogeneous diagnostic yield. For pediatric populations with specific CKD clinical presentation, yields range from 42 to 58% [31; 32], and in adults the yields range from 11 to 36.5% [31; 33; 34]. The corresponding diagnostic yield for non-specific CKD clinical presentations range from 32 to 52% for pediatric cases [45; 46; 47; 48], 30 to 51% for pediatric/adult [49; 50; 51; 52] and 9.3 to 34% for adult cases [53; 54; 63]. Several retrospective studies did not provide separate outcomes from targeted panel or WES. In these cases, the yield for non-specific clinical presentation patients is 51% in pediatric [57], 31-57% in pediatric/adult [55; 58; 59; 60] and 42% in adult cohorts [56; 61]. Studies Including Direct Comparisons of 2 Technologies  
We identified three studies [54; 71; 72] that directly compared the diagnostic yield of two different technologies for the same population (Table 2). One study [71] reported no statistical differences between an enlarged panel (2703 genes, ClearSeq Inherited Disease Panel-Agilent, Santa Clara, CA, USA) and WES. The other two studies [54; 72] show a significant incremental rate (5% and 10%) of WES compared to targeted panel. The main difference between the 3 studies is expressed by the type of targeted panels used. [PERSON] et al. [71] conducted analyses on a large panel of 2703 genes, whereas [PERSON] et al. [72] and [PERSON] et al. [54] employed smaller, selected phenotype-specific targeted panels. [PERSON] et al. and [PERSON] et al. both reported significant differences in diagnostic yield between targeted panels and WES. However, diagnostic yield is directly associated with the correct selection of a targeted panel based on clinical presentation. Therefore, incorrect initial diagnostic suspicion can lead to the selection of an incorrect targeted panel, which a broader WES analysis can correct. In the [PERSON] et al. [72] study, the diagnoses identified through WES analysis only, are on genes included in several \"expanded panels\". Notably, all but 1 are found in the expanded targeted panel employed by [PERSON] et al. [71]. A clinical misdiagnosis or genetic heterogeneity of some conditions can consequently result in the utilization of inappropriate disease-specific panels and misdiagnosis. With the selection of broad panels or genome-wide approaches, this risk is minimized.