Table 1.
A summary of the studies included for the determination of the yield of NGS based approaches in the diagnosis of PIDs. To determine the diagnostic yield of WES when applied in PID patients, literature describing the application of WES, other targeted NGS approaches, and WGS for the diagnosis of cohorts of PID patients were collected. A recent review from Yska et al. described the application of NGS in the diagnosis of PIDs, where a diagnostic yield between 15 and 79% was reported based on 14 studies [5]. To estimate the diagnostic yield of WES in PIDs, PubMed and Embase were used to search for studies describing WES and other NGS approaches for PIDs. The keywords “PID” or “Primary immunodeficiency diseases” were used in combination with “WES,” “NGS,” or “WGS.” Studies describing cohorts of PID patients were included, while studies describing single patients or families were excluded. We expanded the selection from Yska et al. with 10 additional studies. Seven of the studies described the application of WES, two described the application of an NGS approach targeting known PID genes, and one described the application of WGS in the diagnosis of PID patients. From these 24 studies, the sequencing approach, number of genes sequenced using a targeted gene panel or included in the in silico analysis using WES, the number of included patients, and the number and percentage of patients diagnosed were extracted. The average yield of either NGS-based sequencing approaches or a WES-based approach is calculated from the yield of these studies. In two studies that employed WES, the whole exome was analyzed when there were no candidates found in a panel of genes associated with PIDs. The country where patient recruitment was done is also indicated.
| Yield (N (%)) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Authors | Year | Selection | Country | Approach | Genes (N) | N | Diagnostic | Whole exome | Total | Ref |
| Bisgin et al. | 2018 | PID | Turkey | Targeted gene panel | 60 | 37 | 17 (46) | 17 (46) | [47] | |
| Erman et al. | 2017 | SCID | Turkey | Targeted gene panel | 356 | 19 | 6 (33) | 6 (33) | [38] | |
| Rae et al. | 2018 | PID | UK | Targeted gene panel | 242 | 27 | 13 (46) | 13 (46) | [48] | |
| Moens et al. | 2014 | Patients known disease-causing mutation or with agammaglobulinemia without BTK mutations | Sweden + Poland | Targeted gene panel | 179 | 15 | 6 (40) | 6 (40) | [49] | |
| Stoddard et al. | 2014 | PID | USA | Targeted gene panel | 173 | 120 | 18 (15) | 18 (15) | [50] | |
| Nijman et al. | 2014 | CID, ALPS, granulopenia, HLH/XLP | The Netherlands | Targeted gene panel | 170 | 26 | 4 (15) | 4 (15) | [51] | |
| Al-Mousa et al. | 2016 | Suspected PID | Saudi Arabia | Targeted gene panel | 162 | 139 | 35 (25) | 35 (25) | [39] | |
| Yu et al. | 2016 | SCID | USA | Targeted gene panel | 46 | 20 | 14 (70) | 14 (70) | [34] | |
| Kojima et al. | 2016 | PID | Japan | Targeted gene panel | 349 | 59 | 8 (14) | 8 (14) | [52] | |
| Gallo et al. | 2016 | Suspected PID | Italy | Targeted gene panel + WES | 571 | 45 | 7 (16) | 7 (16) | [41] | |
| Abolhassani et al. | 2018 | CID | Iran | Targeted gene panel + WES | 200 | 243 | 189 (79) | 189 (79) | [33] | |
| Suspitsin et al. | 2020 | Pediatric PID patients | Russia | Targeted gene panel | 344 | 333 | 69 (21) | 69 (21) | [53] | |
| Batlle-Maso et al. | 2020 | Autoinflammatory diseases | Spain | WES | 4813 | 22 | 5 (23) | 5 (23) | [42] | |
| Abolhassani et al. | 2019 | Primary antibody deficiency (CVID, agammaglobulinemia, HIGM, IGAD) | Iran | Targeted gene panel + WES | 378 | 126 | 86 (68) | 86 (68) | [37] | |
| Arts et al. | 2019 | PID | The Netherlands, Saudi Arabia, Finland | WES | 302 | 254 | 62 (24) | 10 (4) | 72 (28) | [2] |
| Simon et al. | 2020 | PID | Israel | WES | ? | 106 | 74 (70) | 74 (70) | [36] | |
| Stray-Pedersen et al. | 2017 | PID | USA + Norway | WES | 475 | 278 | 110 (40) | 110 (40) | [35] | |
| Okano et al. | 2020 | PID patients with severe symptoms with negative previous genetic targeted screening | Japan | WES | 430 | 136 | 36 (26.5) | 36 (26.5) | [54] | |
| Maffucci et al. | 2016 | CVID | USA | WES | 269 | 50 | 15 (30) | 15 (30) | [55] | |
| Rudilla et al. | 2019 | PID | Spain | WES | 260 | 61 | 12 (20) | 7 (11) | 19 (31) | [8] |
| Borghesi et al. | 2020 | Pediatric PID patients with sepsis | Switzerland | WES | 240 | 176 | 35 (20) | 35 (20) | [56] | |
| DeValles-Ibanez et al. | 2018 | Pediatric CVID patients | Spain | WES | 16 | 36 | 5–8 (15–24) | 5–8 (15–24) | [57] | |
| Mukda et al. | 2017 | HLH | Thailand | WES | 12 | 25 | 12 (48) | 12 (48) | [43] | |
| Thaventhiran et al. | 2020 | PID | UK | WGS | NA | 886 | 91 (10.3) | 91 (10.3) | [18] | |
ALPS autoimmune lymphoproliferative syndrome, BTK Bruton’s tyrosine kinase, (S)CID (severe) combined immunodeficiency, CVID common variable immunodeficiency, HIGM hyper immunoglobulin M syndrome, HLH hemophagocytic lymphohistiocytosis, IGAD immunoglobulin A deficiency, NA not applicable, PID primary immunodeficiency, WES whole exome sequencing, XLP X-linked lymphoproliferative disease.