TABLE. 2.
Summary of included studies. Patient, cohort, and test characteristics are summarized per phenotype category. When data were missing for one of these characteristics, this was not included in the table. When >50% of studies had a missing value, this was reported in the table, next to a summary of the values that were present. Diagnostic yield is presented in tested cohort and extrapolated to larger (clinical) cohort; in this N/A means not applicable because already entire clinical cohort is reported. Also, the percentage of diagnostic yield that is explained by CNVs is summarized. References are listed in Supplementary Table 3.
| Phenotype | Number of studies* | Number of population (range) | Pediatric/adult (time of study) | Family history (% range) | Consang. (% range) | Extrarenal features (% range) | Mean/median age of onset | Adult‐onset (% range) | ESKD (% range) | Number of studies per variant type | Number of genes analyzed | Diagnostic yield (% range) | Extrapolated larger cohort (% range) | Percentage explained by CNV (% range) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ADKTD | 4 | 56–585 | Adult or NR (in 2/4) | 54.4–72.4% | NR | NR | 45 y, rest NR | NR | 42.9–67.4% | 2 ‐ SNVs 2 ‐ both | 1–5 | 31.0–62.5% | 0.9–30.3%, NR in 1 | 0–1.3% |
| Positively impacting diagnostic yield within one study: Family history; ESKD | ||||||||||||||
| CAKUT | 25 | 30–650 | Mostly fetuses | 0.6–50% | 0–100%, NR in 18/25 | 0–100% | N/A | 0% | 15.6–42.6, NR in 21/25 | 7 ‐ SNVs 11 ‐ CNVs 7 ‐ both | 2–404 or genome/exome wide | 1.3–72.2% | 2.2–27.3%, N/A in 6/12; NR in 3/12 | 0–100%, 100% in 11/25 |
| Positively impacting diagnostic yield within one study: Family history; consanguinity; extrarenal features; CKD5; syndromic and specific phenotypes: MCDK, ciliopathies, multiple urinary tract infections, bilateral anomalies | ||||||||||||||
| Ciliopathies | ||||||||||||||
| ADPKD | 13 | 36–220 | Both | 0–88.4% | NR | 32.6–80.5%, NR in 9/13 | 25–56.7 y | 0–100%, NR in 9/13 | 18.9–57.5% | 3 ‐ SNVs 10 ‐ both | 2–69 or exome wide | 47.9–93.1% | 65.3–70.6%, N/A in 2/6; NR in 1/6 | 1.6–7.1% |
| Positively impacting diagnostic yield within one study: ESKD; disease severity; polycystic liver disease; typical ADPKD | ||||||||||||||
| Other/mixed | 15 | 12–384 | Both | 6.5–77.5% | 0–86.4% | 30–100% | Perinatal ‐ 36 y | 0% in 7/15; NR in 8/15 | 13.6–67.4% | 6 ‐ SNVs 9 ‐ both | 1–4,813 or exome wide | 18.5–97.2% | 22.4–66.7%, NR in 1/2 | 3.0–100% |
| Positively impacting diagnostic yield within one study: Family history; consanguinity; age at diagnosis; phenotype: ARPKD, MKS | ||||||||||||||
| Glomerulopathies | ||||||||||||||
| Nephrotic syndrome | 15 | 36–1,783 | Both, most pediatric | 0–31.0% | 0–75.5% | 0–32.4% | 3–30.3 y | 0–100%, often 0% (in 8/15) | 0–49.6% | 12 ‐ SNVs 3 ‐ both | 3–446 | 11.1–51.0% | 2.0–16.7%, N/A in 1/5; NR in 2/5 | 0–2.7%, NP in 11/15 |
| Positively impacting diagnostic yield within one study: Family history; consanguinity; age of onset; ESKD; lack of response to immunosuppressives; lower posttransplant recurrence | ||||||||||||||
| Other/ mixed | 11 | 40–441 | Both, most adult | 22.3–80.2%, NR in 7/11 | 0–15.5% | 27.8–46.5%, NR in 9/11 | 11–80.2 y | 0–86.4%, NR in 6/11 | 23.8–49.0%, NR in 8/11 | 12 ‐ SNVs 5 ‐ both | 1–109 | 14.1–90.0% | N/A in 3/5; NR in 2/5 | 2.7–21.8%, NP in 5/11 |
| Positively impacting diagnostic yield within one study: Family history; consanguinity; age of onset; number of AS criteria; phenotype: C3G, SRNS | ||||||||||||||
| Nephrolithiasis/urolithiasis | 4 | 48–235 | Both | 47.6–58.3% | 1.9–53.3% | NR | 2–8 y | 0% or NR (in 2/4) | NR | 4 ‐ SNVs | 30–117 | 7.2–37.5% | 6.6–19.1%, N/A in 1/3 | NP |
| Positively impacting diagnostic yield within one study: Family history; consanguinity; age of onset | ||||||||||||||
| Tubulopathies | 5 | 70–1,033 | Both | NR | 4.5%, rest NR | 77.5%, rest NR | 2.2–47.1 y | 0–100% | NR | 1 ‐ SNVs 4 ‐ both | 1–168 | 26.0–71.9% | N/A in 2/2 | 0–63.5% |
| Positively impacting diagnostic yield within one study: Extrarenal features; age of onset; absence of hypomagnesemia | ||||||||||||||
| ESKD | 5 | 50–5,606 | Mostly adult | 22.1%, rest NR (4/5) | 8.7%, rest NR (4/5) | 52.9% rest NR (4/5) | 23 y, rest NR | 30–43.4 y ESKD onset | 0–100% | 100% | 1 ‐ SNVs 4 ‐ both | 20–600 | 0.5–50.9% | 12.5–24.6% | 0–100% |
| Positively impacting diagnostic yield within one study: Family history; consanguinity; extrarenal features; age of onset ESKD | ||||||||||||||
| Mixed kidney disease phenotypes | 18 | 62–3,315 | Both | 9.8–92.0%, NR in 6/18 | 0.3–5.7%, NR in 14/18 | 0–35.9%, NR in 12/18 | 5–42 y, NR in 15/18 | 0–91.6%, NR in 10/18 | 6.3–69.3%, NR in 11/18 | 7 ‐ SNVs 10 ‐ both 1 ‐ NR | 1–4,000, some exome wide | 4.0–72.8% | 6.4–48.8%, N/A in 6/14 | 2.1–20.0% |
| Positively impacting diagnostic yield within one study: Family history; extrarenal features; age of onset; phenotypes: Congenital/cystic disease, unknown origin, ADTKD, TIKD, cystinosis, hematuria, glomerular disease | ||||||||||||||
Abbreviations: aCGH, array comparative genomic hybridization; ADPKD, autosomal dominant polycystic kidney disease; ADTKD, autosomal dominant tubulointerstitial kidney disease; ARPKD, autosomal recessive polycystic kidney disease; AS, Alport syndrome; C3GN, C3 glomerulopathy; CAKUT, congenital anomalies of kidney and urinary tract; CKD, chronic kidney disease; CNV, copy number variations; consang., consanguinity; ESKD, end‐stage kidney disease; MCDK, multicystic dysplastic kidney; MKS, Meckel syndrome; n, number; N/A, not applicable; NP, not performed; NR, not reported; SNV, single nucleotide variant; SRNS, steroid‐resistant nephrotic syndrome; TIKD, tubulointerstitial kidney disease.
References studies: ADTKD: [Ayasreh et al., 2018; Gast et al., 2018; Bleyer et al., 2020; Olinger et al., 2020]; CAKUT: [Sanna‐Cherchi et al., 2012; Hwang et al., 2014; Kohl et al., 2014; Caruana et al., 2015; Nicolaou et al., 2016; Xi et al., 2016; Faure et al., 2016; Fu et al., 2016; Vivante et al., 2017; Bekheirnia et al., 2017; Heidet et al., 2017; Lei et al., 2017; Rasmussen et al., 2018; Unzaki et al., 2018; Boissel et al., 2018; Van Der Ven et al., 2018; Li et al., 2019; Verbitsky et al., 2019; Lin et al., 2019; Cai et al., 2020a; Ahn et al., 2020; Lei et al., 2020; Zhou et al., 2020; Cai et al., 2020b; Zhou et al., 2021]; ciliopathies ADPKD: [Rossetti et al., 2012; Hwang et al., 2016; Jin et al., 2016; Kinoshita et al., 2016; Xu et al., 2018; Fujimaru et al., 2018; Zhang et al., 2019; Mochizuki et al., 2019; Mantovani et al., 2020; Schönauer et al., 2020; Mallawaarachchi et al., 2021; Nielsen et al., 2021; Durkie et al., 2021]; ciliopathies other/mixed: [Bachmann‐Gagescu et al., 2015; Knopp et al., 2015; Braun et al., 2016; Schueler et al., 2016; Al‐Hamed et al., 2016; Lindstrand et al., 2016; Vilboux et al., 2017; Stokman et al., 2018; Szabó et al., 2018; Al Alawi et al., 2019; Liang et al., 2020; Obeidova et al., 2020; Yue et al., 2020; Al Alawi et al., 2020; Benson et al., 2021]; glomerulopathies nephrotic syndrome: [McCarthy et al., 2013; Al‐Hamed et al., 2013; Kari et al., 2013; Giglio et al., 2015; Trautmann et al., 2015; Sadowski et al., 2015; Bierzynska et al., 2017; Wang et al., 2017a, 2017b; Warejko et al., 2018; Tan et al., 2018; Bezdíčka et al., 2018; Gribouval et al., 2018; Landini et al., 2020; Nagano et al., 2020]; glomerulopathies other/mixed: [Fallerini et al., 2014; Morinière et al., 2014; Nabais Sá et al., 2015a, 2015b; Gast et al., 2016; Bu et al., 2016; Sen et al., 2017; Yao et al., 2019; Schapiro et al., 2019; Yamamura et al., 2019; Ozdemir et al., 2020]; nephrolithiasis/urolithiasis: [Daga et al., 2018; Amar et al., 2019; Ziyadov et al., 2021; Zhao et al., 2021]; tubulopathies: [Palazzo et al., 2017; Ashton et al., 2018; Adalat et al., 2019; Hureaux et al., 2019; Mori et al., 2021]; ESKD: [Snoek et al., 2018; Mann et al., 2019; Ottlewski et al., 2019; Schrezenmeier et al., 2021; Snoek et al., 2022]; mixed kidney disease phenotypes: [Alkanderi et al., 2017; Mallett et al., 2017; Lata et al., 2018; Bullich et al., 2018; Groopman et al., 2019; Connaughton et al., 2019; Rao et al., 2019; Thomas et al., 2020; Benson et al., 2020; Riedhammer et al., 2020; Murray et al., 2020; Jayasinghe et al., 2021; Mansilla et al., 2021; Domingo‐Gallego et al., 2022; Oh et al., 2021; Tanudisastro et al., 2021; Amlie‐Wolf et al., 2021; Vaisitti et al., 2021].