Table 2.
Information on pre-whole exome sequencing a priori clinical diagnosis and post- whole exome sequencing molecular genetic diagnosis in the 42 families in whom pathogenic or likely pathogenic mutations in known monogenic chronic kidney disease genes were identified post WES. All families with a molecular genetic diagnosis were classified as pathogenic or likely pathogenic as per the ACMG guidelines (last column). In families in whom segregation was not possible (column 12) AND the exact mutation was not previously described (last column), the variant was considered a variant of uncertain significance (Supplementary Table S1). In the case of a compound heterozygous mutation, at least one of the alleles were classified as either pathogenic or likely pathogeni
| Fam. ID |
Ind. ID |
A priori
clinical Dx pre- WES (PRD codeŦ) |
Reported clinical phenotype |
Extra-renal features |
Age at 1st Dx of CKD ESKD [years] |
Sex | Inclusion criteriaa |
Molecular genetic Dx post WES #OMIMb |
Genotype (Inheritance) |
WES confirm clinical Dxc |
WES correct clinical Dxc |
WES establish new clinical Dxc |
c. changed
p. changee [evolutionary conservationf] |
Zygosity Segregation |
PP2g
SIFTh MTi |
gnom ADj |
ACMGk
HGMDl ClinVarm |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CYSTIC KIDNEY DISEASE (Supplementary Table S6) | |||||||||||||||||
| P13 | 65 | NPHP (2836) | Small, cystic kidneys | Retinitis pigmentosa Mild learning disability | 2 27 |
M | Fam Hx | Mainzer-Saldino syndrome # 266920 | IFT140 (AR) | ✓ | c.634G>A p.Gly212Arg (D.m.) | hom Fa=het, Ma=het Aff sibs=hom Unaff sibs=het | 0.917 Del. D.C. | 0/15/277150 | Path. DM Path. | ||
| 60 | NPHP(2836) | Small, cystic kidneys | 5 12 |
F | Fam Hx | Mainzer-Saldino syndrome # 266920 | IFT140 (AR) | c.634G>A p.Gly212Arg (D.m.) | 0.917 Del. D.C. | 0/15/277150 | Path. DM Path. | ||||||
| P80 | 60 | NPHP(2836) | Small, cystic kidneys | / | 21 21 |
F | Fam Hx | Nephron-ophthisis 1, juvenile # 256100 | NPHP1 (AR) | ✓ | c.555_556insA p.Pro186Thrfs*2 | Hom Fa=NA, Ma=NA Aff sibs=hom Unaff sib=het | / | / | Path. DM / | ||
| 61 | NPHP(2836) | Small, cystic kidneys | / | 11 12 |
M | Fam Hx | Nephron-ophthisis 1, juvenile # 256100 | NPHP1 (AR) | c.555_556insA p.Pro186Thrfs*2 | / | / | Path. DM / | |||||
| P389 | 23 | NPHP (2836) | BL echogenic kidneys | Renal tubular acidosis post-transplant | 8 16 |
M | Extrarenal | Nephron-ophthisis 1, juvenile # 256100 | NPHP1 (AR) | ✓ | c.1027G>A p.Gly343Arg (C.i.) | hom Fa=NA, Ma=NA | 1.00 Del. D.C. | 0/32/276716 | Path. DM Path. | ||
| P324 | 12 | NPHP(2836) | BL echogenic kidneys | Intellectual disability Retinitis pigmentosa Diabetes mellitus Obesity | 20 36 |
F | Extrarenal | Bardet-Biedl syndrome 9 # 615986 | BBS9 (AR) | ✓ | c.542C>G p.Pro181Arg (D.m.) | hom Fa=NA, Ma=NA | 0.99 Del./ | 0/1/246048 | Path. DM / | ||
| P231 | 62 | Cystic KD (2794) | Small kidneys with subcortical cysts | / | 8 40 |
M | Fam Hx | Polycystic kidney disease 4 # 263200 | PKHD1 (AR) | ✓ | c.5221 G>A p.Val1741 Met (C.e.) | hom Fa=NA, Ma=NA Aff. sib=hom | 0.76 Del. D.C. | 0/9/276648 | Path. DM Conflicting | ||
| 64 | / | 38 41 |
F | Fam Hx | Polycystic kidney disease 4 # 263200 | PKHD1 (AR) | c.5221 G>A p.Val1741 Met (C.e.) | 0.76 Del. D.C. | 0/9/276648 | Path. DM Conflicting | |||||||
| P317 | 48 | Cystic KD (2794) | Normal size, cystic kidneys | Conqenital Hepatic Fibrosis | 46 52 |
F | Fam Hx | Polycystic kidney disease 4 # 263200 | PKHD1 (AR) | ✓ | c.2702A>C p.Asn901Thr (X.t.) | Comp. het Fa=NA, Ma=NA Unaff. =single het | 0.60 Del. P.M. | 0/5/246108 | VUS Gene/ | ||
| c.107C>T p.Thr36Met (D.r.) | 0.97 Del. D.C. | 0/142/277030 | Path. DM Path. | ||||||||||||||
| P322 | 11 | Unknown (3555) | BSK | Retinitis pigmentosa Dextrocardia Cholestatic liver dysfunction | 62 70 |
F | Extrarenal | Short-rib thoracic dysplasia 3 with or without Polydactyly # 613091 | DYNC2H1 (AR) | ✓ | c.12431C>G p.Pro4144Arg (C.i.) | Comp. het Fa=NA, Ma=NA | 0.97 Del. D.C. | 0/3/276472 | VUS Gene Likely Path. & uncertain / | ||
| DYNC2H1 (AR) | c.10063+2T>G 100% ESS | / | 0/3/227450 | Path. DM at same position Path. | |||||||||||||
| P105 | 58 | Unknown (3555) | BSK | / | 19 19 |
F | Fam Hx | Nephronophthisi s 1, juvenile # 256100 | NPHP1 (AR) | ✓ | c.555_556insA p.Pro186Hisfs*2 | hom Fa=NA, Ma=NA | / | / | Path. DM Path. | ||
| SYNDROMIC CAKUT (Supplementary Table S7) | |||||||||||||||||
| B2330 | 12 | CAKUT (1625) | R RHD Nephrectomy | Seizure disorder | 0 14 |
M | Fam Hx | Syndromic CAKUT # 244200 | PROKR2 (AD) | ✓ | c.332T>G p.Met111 Arg (X.t) | het Fa=NA, Ma=WT (Affection status Fa unknown) | 0.88 Tol. D.C. | 0/1/246266 | Likely Path. DM/ | ||
| B2481 | 83 | CAKUT (1625) | Unilateral RA | Postaxial Polydactyly Inguinal hernia | 0 12 |
M | Extrarenal | Ulnar-mammary syndrome # 181450 | TBX3 (AD) | ✓ | c.915del p.Asp305Glufs*18 | het Fa=NA, Ma=WT (Affection status Fa unknown) | / | / | Path. Gene / | ||
| B2463 | 96 | CAKUT (1673 & 1706) | BL hydronephrosis/ureter, neurogenic bladder R kidney 22cm L kidney 35cm | Height 195cm Joint hypermotility Saddle nose Gum hypertrophy Downslantina palpebral fissures Hiah arch palate Hammer toes Pes planus | 0 CKD only |
F | Extrarenal | Marfan syndrome (Syndromic CAKUT) # 154700 | FBN1 (AD) | ✓ | c.4888C>T p.Gin 1630* | het Fa=NA, Ma=NA | / | / | Path. DM Path. | ||
| B2328 | 44 | NPHP(2836) | BL echogenic kidneys | Craniosynostosis Mild learning disability | 0 18 |
F | Extrarenal | Greig cephalo-polysyndactyly # 175700 | GLI3 (AD) | ✓ | c.539G>A p.Arg180Gln (D.r.) | het Fa=het, Ma=WT (Affection status Fa unknown) | 0.89 Del. D.C. | 0/14/276690 | Likely Path. Gene/ | ||
| B2454 | 13 | NPHP(2836) | PresumedNPHP Renal Bx -TIN | Hypothyroid Retinitis pigmentosa | 30 CKD only |
M | Extrarenal | Di George syndrome # 188400 | TBX1 (AD) | ✓ | c.1309C>T p.Pro437Ser (D.r.) | het Fa=NA, Ma=NA | 1.00 Tol. D.C. | 0/19/211848 | Likely Path. Gene/ | ||
| P320 | 4 | Cystic KD (2794) | Normal size cystic kidneys | Mild intellectualdisability Macrocephalv Hyperkeratosis Lentiaines | 50 CKD only |
M | Fam Hx | Cardiofacio-cutaneous syndrome # 615280 | MAP2K2 (AD) | ✓ | c.692G>T p.Arg231Leu (D.m.) | het Aff Fa=het, Unaff Ma=NA | 1.00 Del. D.C. | / | Likely Path. Gene Likely Path. | ||
| 73 | Cystic KD (2794) | Normal size cystic kidneys plus VUR | 20 CKD only |
F | Fam Hx | MAP2K2 (AD) | c.692G>T p.Arg231 Leu (D.m.) | 1.00 Del. D.C. | / | Likely Path. Gene Likely Path. | |||||||
| P198 | 102 | Unknown (3555) | CKD-aetiology unknown Renal Bx ND | Hypertension Diabetes mellitus Depression | 36 CKD only |
F | Fam Hx | Wolfram-like syndrome, autosomal dominant # 614296 | WFS1 (AD) | ✓ | c.2654C>T p.Pro885Leu (D.m.) | het Fa=NA, Ma=NA Aff.=het | 1.00 Del. D.C. | 0/4/244868 | Likely Path. Gene Likely Path. | ||
| B2479 | 75 | Unknown (3564) | BL small kidneys (renal Bx FSGSquery secondary) | Gout Retinitis Pigmentosa Anemia Diabetes mellitus Pseudotumour cerebri | 2 15 |
M | Extrarenal | Fanconi anemia, complementation group I # 609053 | FANCI (AR) | ✓ | c.217A>T p.lle73Phe(D.r.1) | hom Fa=NA, Ma=NA | 0.81 Del. D.C. | 0/4/277214 | Likely Path. Gene/ | ||
| ISOLATED CAKUT (Supplementary Table S8) | |||||||||||||||||
| P306 | 92 | CAKUT (1618) | VUR R native nephrectomy | / | 3 12 |
F | Fam Hx | Renal cysts and diabetes syndrome # 137920 | HNF1B (AD) | ✓ | c.1333 1334delGC p.Ala445fs*105 | het Aff sibs=het Unaff sibs=WT | / | / | Path. / / | ||
| B2482 | 98 | CAKUT (1687 & 1618) | PUV BL VUR | / | 0 9 |
M | Neither | CAKUT*611559 | UPK3A (AD) | ✓ | c.227C>A p.Ser76* | het Fa=NA, Ma=NA | / | 0/21/246014 | Path. ?DM / | ||
| P69 | 59 | CAKUT (3517) | Unilateral RA | / | 21 37 |
M | Fam Hx | Papillorenal syndrome # 120330 | PAX2 (AD) | ✓ | c.491 C>A p.Thrl 64Asn (D.r.) | het Fa=NA, Ma=NA | 0.03 Del. D.C. | 0/45/223294 | Path. DM/ | ||
| P307 | 77 | CAKUT (1618) | VUR | / | 42 46 |
M | Fam Hx | Papillorenal syndrome # 120330 | PAX2 (AD) | ✓ | c.70G>C p.Gly24Arg (D.m.) | het Aff Fa=het Unaff. Ma=WT Aff sibs=het Unaff sibs=WT | 1.00 Del. D.C | / | Path. DM/ | ||
| 50 | CAKUT (1618) | VUR | / | 18 25 |
F | Fam Hx | PAX2 (AD) | c.70G>C p.Gly24Arg (D.m.) | 1.00 Del. D.C | / | Path. DM/ | ||||||
| 94 | CAKUT (3517) | Unilateral RA | / | 29 29 |
F | Fam Hx | PAX2 (AD) | c.70G>C p.Gly24Arg (D.m.) | 1.00 Del. D.C | / | Path. DM/ | ||||||
| P162 | 99 | CAKUT (1618) | VUR | / | 50 51 |
M | Fam Hx | Fraser Syndrome # 617666 | FREM2 (AR) | ✓ | c.3661 C>T p.Pro1221Ser (C.i.) | Comp. het Aff sib = comp. het, Unaff sib=single het | 1.00 Del. D.C. | 0/16/277168 | Likely Path. Gene/ | ||
| FREM2 (AR) | c.2533C>T p.His845Tyr (D.r.) | 0.01 Del./ | / | Likely Path. Gene/ | |||||||||||||
| B2342 | 44 | TIKD(1897) | Renal Bx -TIN | Diabetes mellitus Annular pancreas | 37 40 |
F | Fam Hx | Renal cysts and diabetes syndrome # 137920 | HNF1B (AD) | ✓ | c.544+3 544+6 del 75% ESS | het Aff sib = het Unaff sib= WT | / | / | Likely Path. Gene/ | ||
| 63 | TIKD(1897) | Renal Bx -TIN | Diabetes mellitus | 42 CKD only |
M | Fam Hx | HNF1B (AD) | c.544+3 544+6 del 75% ESS | / | / | Likely Path. Gene/ | ||||||
| CHRONIC GLOMERULONEPHRITIS (Supplementary Table S9) | |||||||||||||||||
| B2427 | 56 | CAKUT (1625) | Haematuria BLRHD | / | 3 CKD only |
M | Neither | Alport syndrome # 104200 | COL4A3 (AD) | ✓ | c.4981 C>T p.Arg1661Cys (D.m.) | het Fa = NA, Unaff Ma=het | 1.00 Del. D.C. | 1/103/277100 | Path. DM Path. & Likely Path. | ||
| B2347 | 17 | Unknown (3564) | Haematuria Renal Bx indeterminate | / | 12 48 |
F | Fam Hx | Alport syndrome # 104200 | COL4A3 (AD) | ✓ | c.2452G>A p.Gly818Arg (D.m.) | het Fa=NA, Ma=NA | 1.00 Del. D.C | / | Likely Path. DM Path. | ||
| P241 | 63 | Unknown (3564) | Renal Bx indeterminate | / | 33 CKD only |
F | Fam Hx | Alport syndrome # 301050 | COL4A5 (XLD) | ✓ | c.2396G>A p.Gly799Asp (C.e.) | het Fa=NA, Ma=NA | 1.00 Del. D.C. | / | Likely Path. Gene/ | ||
| P58 | 86 | Unknown (3564) | Renal Bx indeterminate, HTN | / | 23 52 |
M | Fam Hx | Alport syndrome # 301050 | COL4A5 (XLD) | ✓ | c.1423+1 G>T 100% ESS | hemi Fa=NA, Ma=NA | / | / | Path. DM Path. | ||
| P100 | 30 | Unknown (3564) | Renal Bx indeterminate | Deafness Glaucoma Recurrent pneumonia | 30 40 |
F | Fam Hx | Alport syndrome # 301050 | COL4A5 (XLD) | ✓ | c.2605G>A p.Gly869Arg (C.e.) | het/hemi Fa=NA, Aff Ma=het Aff sib = hemi | 1.00 Del. D.C. | / | Path. DM Path. | ||
| 16 | Unknown (3564) | Renal Bx indeterminate | Hearina impairment | 17 20 |
M | Fam Hx | COL4A5 (XLD) | c.2605G>A p.Gly869Arg (C.e.) | 1.00 Del. D.C. | / | Path. DM Path. | ||||||
| B2453** | 80 | Microscopic haematuria (3712) | Hypokalemic metabolic alkalosis/Bartter syndrome (3085) | / | 3 CKD only |
M | Extrarenal | Alport syndrome # 301050 | COL4A5 (XLD) | 2 molecular Dx - see purple segment below | c.2692A>G p.Met898Val (D.r.) | hemi Fa=NA, Ma=NA | 0.01 Tol. D.C. | 0/28/57/198228 | Path. DM / | ||
| P640** | 2008 | ChronicGN (1377) | Microscopic hematuria Normal renal Bx | Low complement (C3) levels | 20 Normal renal function |
M | Fam Hx | Susceptibility to atypical haemolytic uraemic syndrome # 612925 | C3 (AD) | 2 molecular Dx - see green segment below | c.4534C>T p.Arg1512Cys (M.m.) | het Aff. Fa=het Aff. sib=het Unaff. Ma=WT Unaff. sib=WT | 0.65 Del. D.C. | 0/2/246248 | Likely Path. Gene/ | ||
| 82 | ChronicGN (3749) | No renal Bx performed | Low complement (C3) levels | 20 30 |
M | Fam Hx | C3 (AD) | c.4534C>T p.Arg1512Cys (M.m.) | 0.65 Del. D.C. | 0/2/246248 | Likely Path. Gene/ | ||||||
| TUBULO-INTERSTITIAL KIDNEY DISEASE (Supplementary Table S6) | |||||||||||||||||
| B2337 | 52 | TIKD(1897) | Renal Bx -TIN | Uveitis Mucosal ulcers | 42 CKD only |
M | Fam Hx | Hyperuricemic nephropathy # 162000 | UMOD (AD) | ✓ | c.317G>A p.Cys106Tyr (X.t.) | het Fa=NA, Ma=NA Aff. sib= het | 1.00 Del. D.C. | / | Path. DM Uncertain | ||
| 53 | TIKD(1897) | Renal Bx -TIN | Hyperuricemia | 42 CKD only | M | Fam Hx | Hyperuricemic nephropathy # 162000 | UMOD (AD) | c.317G>A p.Cys106Tyr (X.t.) | 1.00 Del. D.C. | / | Path. DM Uncertain | |||||
| P193 | 83 | Unknown (3555) | BSK | / | 20 CKD only |
F | Fam Hx | Hyperuricemic nephropathy # 162000 | UMOD (AD) | ✓ | c.280T>C p.Cys94Arg (D.r.) | het Fa=NA, Ma=NA | 1.00 Del. D.C. | / | Likely Path. Gene/ | ||
| P232 | 60 | Unknown (3564) | Renal Bx indeterminate | Hyperuricemia | 8 18 |
M | Fam Hx | Hyperuricemic nephropathy # 162000 | UMOD (AD) | ✓ | c.1382C>A p.Ala461 Glu (X.t.) | het Fa=NA, Ma=NA | 1.00 Tol. D.C. | / | Path. DM Likely Path. | ||
| P88 | 47 | Unknown (3555) | BSK Renal Bx-insufficient tissue | Bronchiectasis Liver dysfunctionNon-melanomatous cancers | 44 45 |
M | Fam Hx | Karyomegalic interstitial nephritis # 614817 | FAN1 (AR) | ✓ | c.2590C>T p.Gln864* | Comp. het Fa=het, Ma=het Aff. sibs=comp het Unaff. sibs=het | / | 0/1/246242 | Path. Gene/ | ||
| c.2774_2775delTT p.Leu925fs | / | 0/10/267846 | Path. Gene/ | ||||||||||||||
| 38 | Unknown (3555) | BSK Renal Bx-insufficient tissue | Metastatic lung cancer | 33 38 |
F | Fam Hx | FAN1 (AR) | c.2590C>T p.Gln864* | / | 0/1/246242 | Path. Gene/ | ||||||
| c.2774_2775delTT p.Leu925fs | / | 0/10/267846 | Path. Gene/ | ||||||||||||||
| RENAL TUBULOPATHY (Suoolementary Table S10) | |||||||||||||||||
| B2457 | 78 | CAKUT (1625 & 2476) | BLRHD BL renal vein thrombosis Hypernatremia/Dehydration | / | 0 10 |
M | Neither | Nephrogenic diabetes insipidus # 125800 | AQP2 (AD) | ✓ | c.782C>T p.Ser261 Leu (X.t.) | het Fa=NA, Ma=NA | 0.99 Del.D.C. | 0/4/228000 | Likely Path. Gene/ | ||
| B2467 | 35 | Unknown (3564) | Hypertension CKD Renal Bx indeterminate | / | 26 CKD only |
F | Fam Hx | Pseudohypo-aldosteronism -hypertensive CKD # 614491 | WNK4 (AD) | ✓ | c.506C>T p.Pro169Leu (D.r.) | het Fa=NA, Ma=NA | 0.69 Del.D.C. | / | Path. DM/ | ||
| B2350** | 32 | Bartter syndrome (3085) | Hypokalemic metabolic alkalosis | Gout | 17 38 |
F | Fam Hx | Bartter syndrome # 607364 | CLCNKB (AR) | ✓ | c.226C>T p.Arg76* | hom Fa=NA, Ma=NA | / | 0/3/246064 | Path. DM/ | ||
| B2453** | 80 | Bartter syndrome (3085) | Hypokalemic metabolic alkalosis | Microscopic hematuria | 3 CKD only |
M | Extrarenal | Bartter syndrome # 607364 | CLCNKB (AR) | ✓ | c.226C>T p.Arg76* | hom Fa=NA, Ma=NA | / | 0/3/246064 | Path. DM/ | ||
| NEPHROLITHIASIS/NEPHROCALCINOSIS (SuDDlementarv Table S11) | |||||||||||||||||
| B2344 | 78 | Unknown (3564) | Renal Bx indeterminate | Gout | 25 CKD only |
M | Extrarenal | Cystinuria # 220100 | SLC3A1 (AD) | ✓ | c.1799G>A p.Gly600Glu (D.m.) | het Fa=NA, Ma=NA Aff. = het | 1.00 Del D.C. | 0/21/276676 | Likely Path. DM/ | ||
| P318 | 50 | Unknown (3555) | BSK | Intellectual disability Finaer and wrist swell inq Seizure disorder | 41 CKD only |
M | Fam Hx | Lowe syndrome # 309000 | OCRL (XL) | ✓ | c.1567G>A p.Asp523Asn (S.c.) | hemi Unaff. Fa=NA Unaff. Ma=het | 1.00 Del. D.C. | / | Path. DM/ | ||
| P182 | 602 | Unknown (3555) | BSK | Hypophosphatemia Bony pain multiple fractures Bony spurs & sclerosis | 51 55 |
M | Fam Hx | Dent disease # 300009 | CLCN5 (XL) | ✓ | c.1938del p.Phe646Leufs*10 | hemi Fa=NA, Ma=NA | / | / | Likely Path. Gene/ | ||
| B2340 | 15 | Unknown (3555) | BSK | (Son has nephrolithiasis) | 60 CKD only |
F | Fam Hx | Dent disease # 300009 | CLCN5 (XL) | ✓ | c.925C>T p.Arg309Cys (D.r.) | het Aff. son=hemi Fa=NA, Ma=NA | 0.92 Del. D.C. | 0/1/6/193605 | Likely Path. Gene/ | ||
| STEROID RESISTANT NEPHROTIC SYNDROME (Supplemental Table S12) | |||||||||||||||||
| KF4 | 16 | Chronic GN (1377) | Renal Bx indeterminate | / | 74 78 |
F | Fam Hx | Focal segmental glomerulosclerosis # 613237 | INF2 (AD) | ✓ | c.653G>A p.Arg218Gln (X.t.) | het Unaff. Fa=NA, Aff. Ma=het | 1.00 Del. D.C. | / | Path. DM Path. | ||
| 15 | Chronic GN (1377) | Renal Bx-indeterminate | Gout | 52 55 |
F | Fam Hx | INF2 (AD) | c.653G>A p.Arg218Gln (X.t.) | 1.00 Del. D.C. | / | Path. DM Path. | ||||||
| P640** | 83 | Chronic GN (1349) | Renal Bx-indeterminate | Normal complement (C3) levels | 20 23 |
F | Fam Hx | Focal segmental glomerulosclerosis # 613237 | INF2 (AD) | ✓ | c.353T>A p.llel 18Asn(D.r.) | het Aff. Fa=het Aff. sib=het Unaff. Ma=WT Unaff. sib=WT | 1.00 Del. D.C. | / | Likely Path. Gene/ | ||
| 82 | ChronicGN (3749) | Renal Bx ND | Low complement (C3) levels | 20 30 | M | Fam Hx | INF2 (AD) | c.353T>A p.llel 18Asn (D.r.) | 1.00 Del. D.C. | / | Likely Path. Gene/ | ||||||
| RARE MONOGENIC CKD genes (MISCELLANEOUS CATEGORY) (Supplementary Table S13) | |||||||||||||||||
| B2327 | 66 | Cystic KD (2794) | Normal size cystic kidneys | Liver dysfunction Unexplained seizures, L facial weakness without definite patholoav noted on brain imaaina, unexplained abdominal symptoms, photophobia | 1 6 |
F | Extrarenal | Fabry Disease # 301500 | GLA (XL) | ✓ | c.352C>T p.Argl 18Cys het(X.t.2) | het Fa=NA, Ma=NA | 0.99 Del. P.M. | 0/15/43/200247 | Likely Path. DM Conflicting | ||
A priori clinical diagnosis, the clinical diagnosis of chronic kidney disease defined pre-WES as per the primary nephrologist’s referral; A, adenine; AD, autosomal dominant; Aff, affected; AR, autosomal recessive; BL, bilateral; BSK, bilateral small kidneys; Bx, biopsy; C, cytosine; c. change, nucleotide change; CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; cm, centimeter; comp, compound; conflicting, multiple submitters have provided assertion criteria to the ClinVar database but there are conflicting interpretations; del, deletion; delins, deletion insertion; Del., Deleterious; D.C., Disease Causing; DM, disease mutation; Dx, diagnosis; ESKD, end stage kidney disease; ESS, essential splice site; F, female; Fa, father; Fam. ID, unique family identifier; fs, frameshift mutation; FSGS, focal segmental glomerulosclerosis; G, guanine; GN, glomerulosclerosis; hemi, hemizygous; het, heterozygous; hom, homozygous; HTN, hypertension; Ind. ID, unique individual identifier; ins; insertion; KD, kidney disease; L, left; M, male; Ma, maternal; NA, not available; ND, not done; NPHP, nephronophthisis; p. change, amino acid change; Path., pathogenic; P.M., Polymorphism; PRD, primary renal diagnosis; PUV, posterior urethral valve; R, right; RA, renal agenesis; RHD, renal hypodysplasia; sibs, sibling(s); unknown, CKD - aetiology unknown; T, thymine; TIKD, tubulo-interstitial kidney disease; TIN, tubulo-interstitial nephritis; Tol., Tolerated; VUR, vesico-ureteric reflux; VUS, variant of uncertain significance; WES, whole exome sequencing; WT, wild type; XL, X-linked; XLD, X-linked dominant.
Additional clinical features established post WES, following clinical re-review in full cognizance of the molecular genetic diagnosis are highlighted in bold, underlined text in columns 4 & 5.
indicates additional finding in another category;
nonsense mutation;
Ŧ, ERA-EDTA primary renal disease codes (https://www.era-edta-reg.org/prd.jsp); /, data not available.
Inclusion criteria; Fam Hx, positive family history; Extra-renal, CKD with extra-renal features; Neither, no family history and no extra-renal features
# OMIM, Online Mendelian Inheritance in Man (https://www.omim.org)
Outcome following WES: WES confirm clinical Dx, WES confirmed the clinical diagnosis; WES correct clinical Dx, WES resulted in reclassification/ correction of the clinical diagnosis; WES establish new clinical Dx, WES resulting in establishment of a molecular diagnosis in families with CKD - aetiology unknown.
impact of variant on cDNA level
impact of variant on the amino acid or protein level
evolutionary conservation was assessed across phylogeny over eight species: M.m., Mus musculus; G.g., Gallus gallus; X.t., Xenopus tropicalis; D.r., Danio rerio; C.e., elegans; C.i., Ciona intestinalis; D.m., Drosphilia melanogaster; S.c., Saccharomyces cerevisiae. If conservation is interrupted in one species but otherwise preserved across phylogeny a numerical reference is provided: 1Valine in G. gallus; 2Lysine in M. musculus.
PP2, PolyPhen 2 (http://genetics.bwh.harvard.edu/pph2)
SIFT, Sorting intolerant from tolerant (http://sift.jcvi.org/)
MT, Mutation Taster (http://www.mutationtaster.org)
gnom AD, variant frequencies listed for homozygous/ hemizygous (if applicable)/ heterozygous/ total alleles(http://gnomad.broadinstitute.org/)
ACMG, American College of Human Genetics Standards and Guidelines Classification as pathogenic, likely pathogenic or VUS (Richards Genet Med 17(5):405, 2015)
HGMd, Human Gene Mutation Database; https://portal.biobaseinternational.com/hgmd, If the exact variant has previously been reported on HGMD Professional 2017.2 for the reported phenotype and classified as a pathogenic mutations to be disease causing, variant denoted as “DM”. Variant denoted as “?DM” if the variant is a likely pathogenic mutation to be disease causing but where the author indicated some degree of doubt or subsequent evidence calls the deleterious nature of the variant into question. If the gene but not the exact variant has been reported for the corresponding phenotype “Gene” is indicated in this column.
Clin Var, classification if variant has been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar).