Article Figures & Data
Figures
- Figure 1.
Flow diagram showing mechanism for filtering variants to identify those variants of potential pathogenicity.
- Figure 2.
Comparison of NGS and Sanger sequencing data acquisition Sequencing results for patient 8 and parents in gene COQ2 at nucleotide position c.683A>G (N228S; A, C, E, and G) and nucleotide position c.701delT (L234fsX247; B, D, F, and H). Next generation sequencing showed a heterozygous ns single-nucleotide polymorphism (SNP; A) and a heterozygous deletion (B) in patient 8. Both the non-synonymous (ns) SNP (C) and the deletion (D) were confirmed by Sanger methodology. The mother of the patient was confirmed to be a heterozygous carrier of the nsSNP (E) but not the deletion (F), whereas father did not carry the nsSNP (G) but was found to be heterozygous for the deletion (H).
Tables
Gene Protein Disease Association ACTN4 α-Actinin 4 Familial and sporadic SRNS (adult) ALG1 Asparagine-linked glycosylation 1 Congenital disorder of glycosylation APOL1 Apolipoprotein L1 Increased susceptibility to FSGS CD2AP CD2-associated protein FSGS/SRNS COL4A3 Collagen, type IV, α3 Alport’s disease COL4A4 Collagen, type IV, α4 Alport’s disease COL4A5 Collagen, type IV, α5 Alport’s disease COQ2 Coenzyme Q2 homolog Mitochondrial disease/isolated nephropathy INF2 Inverted Formin-2 Familial and sporadic SRNS LAMB2 Laminin, β2 Pierson syndrome LMX1B LIM homeobox transcription factor 1β Nail patella syndrome MHY9 Nonmuscle myosin heavy chain 9 MYH9-related disease MYO1E Myosin IE Familial SRNS NPHS1 Nephrin Congenital nephrotic syndrome/SRNS NPHS2 Podocin Congenital nephrotic syndrome/SRNS PDSS2 Prenyl (decaprenyl) diphosphate synthase, subunit 2 Leigh syndrome PLCe1 Phospholipase C, ε1 Congenital nephrotic syndrome/SRNS PMM2 Phosphomannomutase 2 Congenital disorder of glycosylation PTPRO Protein tyrosine phosphatase, receptor type, O Familial SRNS SCARB2 Scavenger receptor class B member 2 Action myoclonus renal failure syndrome SMARCAL1 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1 Schimke immuno-osseous dysplasia TRPC6 Transient receptor potential cation channel, subfamily C, member 6 Familial and sporadic SRNS (adult) WT1 Wilms tumor 1 Sporadic SRNS (children—may be associated with abnormal genitalia) ZMPSTE24 Zinc metallopeptidase STE24 homolog Mandibuloacral dysplasia Twenty-four genes associated with steroid-resistant nephrotic syndrome (SNRS) of congenital, childhood, or adult onset, familial and sporadic origin, and different syndrome association. SW1/SNF, SWItch/Sucrose Non-Fermentable; MYH9, myosin heavy chain 9, non-muscle; LIM, LIN-11, Islet-1, and MEC-3.
Patient Sex Ethnicity Age at Onset (yr or mo) Familial (Family a, b, c, d, or e) or Sporadic Phenotype Length of Follow-Up (Yr) Current CKD Stage Time to ESRF (mo) Disease Recurrence if Transplanted 1 F NA Birth Fam (a) C 7 1 n/a n/a 2 M In 1 mo S C 6 5 (HD) 42 n/a 3 F W 2 mo S C 3 3 n/a n/a 4 F NA 3 mo Fam (a) C 10 1 n/a n/a 5 M In 3 mo Fam (b) P — — — — 6 F W 11 mo Fam (c) P 13 3 n/a n/a 7 M Pa 1 yr S P 6 5 12 No 8 F W 2 yr S P 2 5 (PD) 6 n/a 9 F W 2 yr Fam (c) P 2 1 n/a n/a 10 M W 2 yr Fam (c) P 11 3 n/a n/a 11 F Mix 2 yr S P 2 1 n/a n/a 12 M In 2 yr S P 9 5 20 Yes 13 F W 2 yr S P 4 5 57 n/a 14 M W 2 yr S P 3 1 n/a n/a 15 M W 2 yr S P 10 5 (Tx) 36 Yes 16 F W 4 yr S SYN 6 5 22 Yes 17 F NA 4 yr S P 3 1 n/a n/a 18 F W 4 yr S P 6 2 n/a n/a 19 M NA 5 yr Fam (d) P 4 1 n/a n/a 20 F W 5 yr S P 2 1 n/a n/a 21 M W 6 yr S P 10 5 (Tx) 24 Yes 22 F W 6 yr S P 3 5 (Tx) 18 Yes 23 F In 6 yr Fam (e) P 3 1 n/a n/a 24 M W 7 yr S P 7 5 (PD) 78 n/a 25 F W 8 yr S P 2 1 n/a n/a 26 M W 9 yr S P 14 1 n/a n/a 27 M W 10 yr S P 6 5 (Tx) 34 Yes 28 F W 10 yr S P 5 1 n/a n/a 29 M NA 10 yr Fam (d) P 4 2 n/a n/a 30 M NA 11 yr Fam (a) P 5 2 n/a n/a 31 M W 12 yr S SYN 5 5 8 No 32 F In 12 yr S P 1 1 n/a n/a 33 F Pa 13 yr S P 1 1 n/a n/a 34 F W 13 yr S P 1 1 n/a n/a 35 F W 14 yr S P 2 1 n/a n/a 36 M W 16 yr S S 2 1 n/a n/a Clinical details per patient. C, congenital nephrotic syndrome; ESRF, end stage renal failure; F, female; Fam, familial; HD, hemodialysis; In, Indian subcontinent; M, male; Mix, mixed Caucasian and Afro Caribbean; NA, North African; n/a, not applicable; P, primary steroid resistance; Pa, Pakistani; PD, peritoneal dialysis; S, sporadic; SYN, syndrome with associated steroid-resistant nephrotic syndrome; Tx, transplanted; W, white.
Gene Variant Patients Affected (Heterozygote Unless Hom-Homozygous) dbSNP Ref. No. (Build 135) MAF If Available or ESP Genotype Count HGMDa (Authors’ Comments) PolyPhen MutPred ACTN4 Arg310Gln 23 rs112545413 A=0.0055 FSGS (but also in controls) Benign 0.459 APOL1 Val369Glu 20 rs143845266 ESP: AT-0.003 TT-0.997 No Probably damaging 0.831 APOL1 Gly247Arg 15 rs146925617 ESP: AG-0.001 GG-0.999 No Benign 0.516 APOL1 Asn403fs 1, 30 rs143830837 No data No n/a n/a CD2AP Pro566Ser 2 Not in dbSNP ESP: TC-0.0002 CC-0.9998 No Benign 0.389 COL4A4 Ala715Val 7 rs76636743 A=0.0014 No Benign 0.282 COL4A4 Ala1558Val 7 Not in dbSNP No data No Unknown 0.418 COL4A4 Arg877Gln 6 rs150979437 ESP: TC-0.005 CC-0.995 No Unknown 0.526 COL4A4 Ser969b 24 (hom) rs35138315 No data Alport syndrome n/a n/a COL4A4 Gly999Glu 23, 29 rs13027659 T=0.0073 No Unknown 0.6 COL4A4 Met1399Leu 17 rs149117087 No data No Unknown 0.508 COQ2 Asn228Ser 8 rs121918232 No data Coenzyme Q10 deficiency Probably damaging 0.75 COQ2 Leu234fs 8 Not in dbSNP No data No n/a n/a INF2 Arg877Gln 7 rs142678449 ESP: AA-0.0004 AG-0.0168 GG-0.9828 No Unknown 0.447 INF2 Glu593Lys 28 Not in dbSNP No data No Unknown 0.502 INF2 Ile685Va 19, 29 Not in dbSNP ESP: GA-0.0002 AA-0.9998 No Unknown 0.527 INF2 Val557Gly 19 Not in dbSNP ESP: GT-0.004 TT-0.996 No Unknown 0.512 LAMB2 Gly1676Ile 33 Not in dbSNP No data No Benign 0.233 LAMB2 Arg575Gln 28 rs61729152 T=0.0087 No Benign 0.566 MYH9 Lys910Gln 23 (hom) Not in dbSNP No data Fechtner syndrome (but also in control) Possibly damaging 0.368 MYH9 Ala1072Thr 2 Not in dbSNP No data No Benign 0.357 MYH9 Lys1775Glu 14 rs145139708 C=0.002 No Benign 0.561 MYH9 Arg1936Gln 10 Not in dbSNP No data No Possibly damaging 0.203 MYO1E Ile531Met 34 rs140447165 C =0.002 No Possibly damaging 0.634 NPHS1 His1174Tyr 21 rs115489112 A=0.0018 No Possibly damaging 0.431 NPHS1 Asn1077Ser 1, 4, 5, 7, 8, 9, 15, 26, 30 (21 hom) rs4806213 C=0.0836 CNS (but also in control) Possibly damaging 0.269 NPHS1 Arg408Gln 16, 26 rs33950747 T=0.0297 CNS (but also in control) Possibly damaging 0.892 NPHS1 Pro264Arg 22, 32, 35, 36 rs34982899 C=0.0105 CNS (in a single patient as a compound het) Benign 0.77 NPHS1 Ala806Gly 2 (hom) Not in dbSNP No data No Possibly damaging 0.805 NPHS1 Glu117Lys 11, 16, 18, 24, 25, 26, 35, 36 (1, 2, 4, 12, 20, 30 hom) rs3814995 T=0.3423 CNS (but also in control) Possibly damaging 0.802 NPHS1 Arg586Gly 1, 4, 30 (hom) Not in dbSNP No data FSGS Benign 0.824 NPHS1 Ala916Ser 6 rs138173172 ESP: AC 0.006 CC 0.994 Reported in 1 patient with minimal change Possibly damaging 0.72 NPHS1 Thr294Ile 9, 10 rs113825926 A=0.0037 Reported in 1 patient with minimal change Benign 0.296 NPHS1 Val1084fs 3 (hom) Not in dbSNP No data CNS n/a n/a NPHS2 Pro20Leu 17 rs74315344 A=0.0014 Nephrotic syndrome, steroid-resistant n/a 0.721 NPHS2 Arg229Gln 6, 10, 27 rs61747728 T=0.0178 FSGS Possibly damaging 0.698 NPHS2 Ala284Val 23 (hom) Not in dbSNP No data Nephrotic syndrome, steroid-resistant Possibly damaging 0.945 NPHS2 Phe344fs 6, 10 Not in dbSNP No data FSGS n/a n/a PLCE1 Arg321b 5 (hom) Not in dbSNP No data FSGS n/a n/a PLCE1 Leu57Phe 19, 29 Not in dbSNP No data No Possibly damaging 0.106 PMM2 Glu197Ala 13 rs34258285 C=0.0119 Congenital disorder of glycosylation 1a (but polymorphism) Benign 0.826 PTPRO His362Arg 34 rs141042273 ESP: AA-0.999 AG-0.001 No Benign 0.392 SMARCAL1 Glu377Gln 12 rs2066518 C=0.0603 Schimke immuno-osseous dysplasia (report not clearly pathogenic) Possibly damaging 0.492 WT1 Ala100Gly 1, 4 (hom) Not in dbSNP No data No Benign 0.723 Variants of note in the exome of 24 genes associated with steroid-resistant nephrotic syndrome (SRNS) sequenced in 36 patients. Includes all variants described in Human Genome Mutation Database (HGMD) professional, all novel variants (not being described in single-nucleotide polymorphisms database [dbSNP] or the 1000 Genomes Project), and all variants with an minor allele frequency (MAF)<1% in the 1000 Genomes Project (http://www.1000genomes.org/node/506; allele frequency) or if not available, Exome Variant Server, National Heart, Lung and Blood Institute Exome Sequencing Project (ESP), Seattle, WA (http://evs.gs.washington.edu/EVS/). Where possible, MutPred and PolyPhen scores are also provided. CNS, congenital nephrotic syndrome; n/a, not available.
↵a Professional release: December of 2011.
↵b Nonsense.
Gene Variant State Patient Familial/Sporadic dbSNP Ref. No. Population Frequency PolyPhen MutPred Definitely pathogenic COL4A4 Ser969a Hom 24 Sporadic rs35138315 No data n/a n/a NPHS1 Arg586Gly Hom 1, 4, 30 Familial Not in dbSNP No data Benign 0.824 NPHS1 Val1084fs Hom 3 Sporadic Not in dbSNP No data n/a n/a NPHS2 Ala284Val Hom 23 Familial Not in dbSNP No data Probably damaging 0.945 PLCE1 Arg321a Hom 5 Familial Not in dbSNP No data n/a n/a Probably pathogenic No data COQ2 Asn228Ser CH 8 Sporadic rs121918232 No data Probably damaging 0.75 COQ2 Leu234fs 8 Not in dbSNP No data n/a n/a NPHS1 Ala806Gly Hom 2 Sporadic Not in dbSNP No data Possibly damaging 0.805 NPHS2 Arg229Gln CH 6, 10 Familial rs61747728 T=0.0178 Possibly damaging 0.698 NPHS2 Phe344fs 6, 10 Not in dbSNP No data n/a n/a Possibly pathogenic APOL1 Val369Glu Het 20 Sporadic rs143845266 ESP: AT-0.003 TT-0.997 Probably damaging 0.831 MYO1E Ile531Met Het 34 Sporadic rs140447165 C =0.002 Probably damaging 0.634 NPHS1 Ala916Ser Het 6 Familial rs138173172 ESP: AC 0.006 CC 0.994 Probably damaging 0.72 NPHS2 Pro20Leu Het 17 Sporadic rs74315344 A=0.0014 n/a 0.721 WT1 Ala100Gly Het & Hom 1, 4 Familial Not in dbSNP No data Benign 0.723 Variants identified by analysis of 24 nephrotic genes according to pathogenicity. Pathogenicity definition as described in the text. dbSNP, single-nucleotide polymorphism database; fs, frame shift; Hom, homozygous; Het, heterozygous; CH, compound heterozygous; n/a, not available.
↵a Nonsense.
Age at Onset (yr) Total Familial Sporadic Variant Identified Definite or Probable Genetic Cause (%) Definitely Pathogenic Probably Pathogenic <2 7 4 3 4 2 86 2–5 11 2 9 0 2 18 >5 18 4 14 3 0 17
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- Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing
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