Genetic screening in adolescents with steroid-resistant nephrotic syndrome
2013; Elsevier BV; Volume: 84; Issue: 1 Linguagem: Inglês
10.1038/ki.2013.93
ISSN1523-1755
AutoresBeata S. Lipska‐Ziętkiewicz, Paraskevas Iatropoulos, Ramona Maranta, Gianluca Caridi, Fatih Özaltın, Ali Anarat, Ayşe Balat, Jutta Gellermann, Agnes Trautmann, Özlem Erdoğan, Bassam Saeed, Sevinç Emre, Radovan Bogdanović, Marta Azócar, Irena Bałasz–Chmielewska, Elisa Benetti, Salim Çalışkan, Sevgı Mır, Anette Melk, Pelin Ertan, Esra Baskın, Helena Jardim, Tinatin Davitaia, Anna Wasilewska, Dorota Drożdż, Maria Szczepańska, Augustina Jankauskienė, Lina María Serna-Higuita, Gianluigi Ardissino, Ozan Özkaya, Elżbieta Kuźma-Mroczkowska, Oğuz Söylemezoğlu, Bruno Ranchin, Anna Medyńska, Marcin Tkaczyk, Amira Peco‐Antić, İpek Akil, Tomasz Jarmoliński, Piotr Adamczyk, Ladislav Dušek, Giacomo D. Simonetti, Faysal Gök, Alaleh Gheissari, Francesco Emma, Rafael T. Krmar, Michel Fischbach, Nikoleta Printza, Eva Šimková, Caterina Mele, Gian Marco Ghiggeri, Franz Schaefer,
Tópico(s)Coagulation, Bradykinin, Polyphosphates, and Angioedema
ResumoGenetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10–20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8–9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome. Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10–20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8–9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome. Steroid-resistant nephrotic syndrome (SRNS) is a heterogeneous disorder caused either by dysregulation of the immune system or by genetic abnormalities affecting podocyte-specific proteins. Knowledge of the underlying pathology has major impact on the treatment and prognosis of the disorder. The genetic heterogeneity and phenotypic variability of SRNS mandates a rational, adapted approach to genetic screening. The age of disease onset is an important predictor of the odds of finding an abnormality in a particular gene linked to SRNS. In recent years, several proposals for genetic screening paradigms have been put forward, which preferentially addressed congenital and infantile onset cases.1.Machuca E. Benoit G. Nevo F. et al.Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome.J Am Soc Nephrol. 2010; 21: 1209-1217Crossref PubMed Scopus (113) Google Scholar, 2.Hinkes B.G. Mucha B. Vlangos C.N. et al.Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).Pediatrics. 2007; 119: e907-e919Crossref PubMed Scopus (357) Google Scholar, 3.Benoit G. Machuca E. Antignac C. Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations.Pediatr Nephrol. 2010; 25: 1621-1632Crossref PubMed Scopus (137) Google Scholar, 4.Santín S. Bullich G. Tazón-Vega B. et al.Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome.Clin J Am Soc Nephrol. 2011; 6: 1139-1148Crossref PubMed Scopus (173) Google Scholar SRNS manifesting at adolescent age was addressed as a subject of minor interest in two recent reports only.3.Benoit G. Machuca E. Antignac C. Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations.Pediatr Nephrol. 2010; 25: 1621-1632Crossref PubMed Scopus (137) Google Scholar,4.Santín S. Bullich G. Tazón-Vega B. et al.Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome.Clin J Am Soc Nephrol. 2011; 6: 1139-1148Crossref PubMed Scopus (173) Google Scholar The current literature suggests that at least five genes should be taken into consideration in adolescent-onset SRNS: NPHS2 in autosomal recessive (AR) and sporadic cases,5.Tsukaguchi H. Sudhakar A. Le T.C. et al.NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.J Clin Invest. 2002; 110: 1659-1666Crossref PubMed Scopus (223) Google Scholar,6.Machuca E. Hummel A. Nevo F. et al.Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant.Kidney Int. 2009; 75: 727-735Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar WT17.Aucella F. Bisceglia L. De Bonis P. et al.WT1 mutations in nephrotic syndrome revisited. High prevalence in young girls, associations and renal phenotypes.Pediatr Nephrol. 2006; 21: 1393-1398Crossref PubMed Scopus (48) Google Scholar in autosomal dominant (AD) and sporadic cases, and TRCP6,8.Heeringa S.F. Möller C.C. Du J. Yue L. et al.A novel TRPC6 mutation that causes childhood FSGS.PLoS One. 2009; 4: e7771Crossref PubMed Scopus (128) Google Scholar ACTN4,9.Kaplan J.M. Kim S.H. North K.N. et al.Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.Nat Genet. 2000; 24: 251-256Crossref PubMed Scopus (1040) Google Scholar and the recently identified INF210.Brown E.J. Schlöndorff J.S. Becker D.J. et al.Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis.Nat Genet. 2010; 42: 72-76Crossref PubMed Scopus (340) Google Scholar in AD cases. In contrast, the occurrence of mutations in the genes NPHS1, PLCE1, MYOE1, and PTPRO in this age group is rather anecdotal.11.Santín S. García-Maset R. Ruíz P. et al.Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis.Kidney Int. 2009; 76: 1268-1276Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Furthermore, APOL1 variants are considered risk factors for focal segmental glomerulosclerosis (FSGS) in young adults, at least in the African-American population.12.Kanji Z. Powe C.E. Wenger J.B. et al.Genetic variation in APOL1 associates with younger age at hemodialysis initiation.J Am Soc Nephrol. 2011; 22: 2091-2097Crossref PubMed Scopus (86) Google Scholar Although most previous studies in SRNS focused on familial cases, the vast majority of adolescent SRNS cases are in fact sporadic. The PodoNet registry study collects clinical and genetic information as well as biomaterials from patients with SRNS across the pediatric age range. With almost 1500 cases from 66 pediatric nephrology centers in 21 countries compiled to date, PodoNet is the largest registry worldwide devoted to this rare disorder (Supplementary Material S1 online). Here, we utilized the PodoNet registry to perform comprehensive screening for genetic causes in an unselected population of 297 SRNS patients with disease onset in the second decade of life, including both sporadic and familial cases. Download .pdf (.05 MB) Help with pdf files Supplementary Material 1 AR cases accounted for ∼25% of Polish, Turkish, and Syrian patients enrolled in the study, whereas family history was positive in no more than 10% of patients from Western Europe and Latin America. A total of 38 (17%) patients (including members of 12 AR families) descended from consanguineous marriages; all of these were from Turkey or the Middle East. The distribution of age at onset and degree of proteinuria was similar in the familial and sporadic forms. On biopsy, patients with familial SRNS showed less frequently minimal change histology (3% vs. 16%, P=0.05) and more commonly mesangioproliferative glomerulonephritis (24% vs. 9%, P TIVS9+4C>TF209NANANoHorseshoe kidneyNoNo response2No datac.1432+4C>TIVS9+4C>TF 46,XY11.5– (2.2 obs)FSGS1.5NoNo uterus, vaginal rest, hypoplastic gonadsYesNo response3No datac.1432+4C>TIVS9+4C>TF 46,XY13.00.75FSGS6.5NoFemale habitus bilateral ovarian dysgerminomaYesNot treated4De novoc.1432+5G>AIVS9+5G>AF 46,XY10.07.7FSGS4.9NoRudimentary uterus and vaginal rest, hypoplastic gonadsYesNo response5De novop.(Arg355*)p.R287XF 46,XX15.62.5NA3At age 3.0 yearsNoneNoNot treated6De novop.(Arg430*)p.R362XF 46,XX12.24.4FSGS8.5At age 1.2 yearsNoneNoNot treated7De novop.(Arg458*)p.R390XF 46,XX15.3– (0.7 obs)FSGS3.9At age 0.8 yearsOvarian cystNoPartial response to CsA8No datap.(Arg458*)p.R390XM 46,XY18.5– (9.3 obs)FSGS8NoPenile hypospadia, hypoplastic scrotum, bilateral abdominal cryptorchidism, rudimentary uterus and vaginal rest, hypoplastic testesYesNot treatedAbbreviations: AD, autosomal dominant; CsA, cyclosporin A; ESKD, end-stage kidney disease; F, phenotypic female; FSGS, focal segmental glomerulosclerosis; NA, not available; M, phenotypic male; obs, clinical observation. Open table in a new tab Table 2Clinical and demographic characteristics of the patients with known mutations or novel sequence variants in the INF2 geneINF2 variantType of mutationNo. of patientsOrigin of mutationEthnicityConsanguinityAge at diagnosis (years)Proteinuria at diagnosis (g/m2/day)Histopathology on last examinationESKDDuration of clinical observation (years)c.653G>Ap.(Arg218Gln)Known mutation1Paternal (AD trait)ItalianNo16.81.0FSGSNo12.2c.658G>Ap.(Glu220Lys)Known mutation1Probably maternalaMother died at age 27 years for post-partum nephritis; no biological sample is available for mutational analysis. (AD trait)ItalianNo13.71.8MCNYes7.0c.1736-6C>TNovel1PaternalTurkishYes10.32.6GGSNo3.5c.2053A>Gp.(Ile685Val)Novel1PaternalTurkishNo14.85.0FSGSNo4.9c.2630G>Ap.(Arg877Gln)Novel2De novo/maternalTurkishNo10.6–14.81.0FSGSNo3.7–4.9Abbreviations: AD, autosomal dominant; ESKD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; GGS, global glomerulosclerosis; MCN, minimal change disease.a Mother died at age 27 years for post-partum nephritis; no biological sample is available for mutational analysis. Open table in a new tab Abbreviations: AD, autosomal dominant; CsA, cyclosporin A; ESKD, end-stage kidney disease; F, phenotypic female; FSGS, focal segmental glomerulosclerosis; NA, not available; M, phenotypic male; obs, clinical observation. Abbreviations: AD, autosomal dominant; ESKD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; GGS, global glomerulosclerosis; MCN, minimal change disease. In all, 5/38 (13%) AR patients and 11/179 (6%) sporadic cases were found to have podocin-associated SRNS. NPHS2-positive patients did not differ from the other adolescents with respect to age at first manifestation, time to end-stage renal disease, histopathology, and degree of proteinuria. FSGS was present in 10 cases, mesangioproliferative glomerulonephritis GN in 2 cases, and minimal change nephropathy and global glomerulosclerosis in 1 case each. Homozygous mutations in NPHS2 were found in 5 (all sporadic) patients and compound heterozygous mutations in 11 patients (Table 3). The most common mutations were as follows: p.Val180Met present in three cases from different ethnic backgrounds (Germany, Italy, and Turkey); p.Ala284Val found in two Chilean and one Portuguese patient; and c.1032delT reported in three adolescents from Northern Poland. No other significant findings with respect to allele distribution was observed in the PodoNet cohort.Table 3Clinical and demographic characteristics of the patients with podocin-related SRNSNPHS2 mutation(s)Type of mutationNo. of patientsEthnicityConsanguinityAge at diagnosis (years)Proteinuria at diagnosis (g/m2/day)Time to ESKD (years)Histopathology on last examination(p.Trp122*);(p.Arg238Ser)Known mutations1TurkishNo15.9NA-(0.8 obs)No data(p.Arg138Gln);(p.Arg138Gln)Known mutation1GermanNo106.9-(3.0 obs)FSGS(p.Arg138Gln);(p.Val180Met)Known mutations1ItalianNo13.65.23.5FSGS(p.Leu169Pro);(p.Leu169Pro)Known mutation1TurkishNo11.86.94.4FSGS(p.Val180Met);(p.Val180Met)Known mutation2Turkish, GermanNo10.616.68.06.02.43.5FSGSFSGS(p.Arg229Gln);(c.451+3A>T)Novel mutation1GermanNo14.8NA-(4.7 obs)MCN(p.Arg229Gln);(p.Ala284Val)Known mutation2Portuguese, ChileanNo10.311.91.6NA-(4.7 obs)1.3MesPGNFSGS(p.Arg229Gln);(p.Ala297Val)Known mutation1PolishNo13.52.43.6MesPGN(p.Arg229Gln);(p.Glu310Lys)Novel mutation1TurkishNo13.11.53.2No data(p.Arg229Gln);(p.His325Tyr)Known mutation1ItalianNo18.85.82.4FSGS(p.Arg229Gln);(c.1032delT)Known mutation3NorthernPolishNoNono14.915.717.63.36.53.3-(10 obs)-(2.7 obs)-(6.4 obs)GGSFSGSFSGS(p.Ala284Val);(p.Ala284Val)Known mutation1ChileanNo12.4NA0.8FSGSAbbreviations: ESKD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; GGS, global glomerulosclerosis; MCN, minimal change disease; MesPGN, mesangioproliferative glomerulonephritis; NA, not available; obs, clinical observation; SRNS, steroid-resistant nephrotic syndrome. Open table in a new tab Abbreviations: ESKD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; GGS, global glomerulosclerosis; MCN, minimal change disease; MesPGN, mesangioproliferative glomerulonephritis; NA, not available; obs, clinical observation; SRNS, steroid-resistant nephrotic syndrome. The patients with homozygous NPHS2 mutations were slightly younger at first manifestation than the compound heterozygous cases (12.2 vs. 14.6 years). Also, the course of disease was more severe among the homozygous NPHS2 cases, 4/5 of whom reached end-stage renal disease within 5 years from initial diagnosis, whereas 55% of compound heterozygous cases were still treated conservatively at this time point. Of the 16 patients with NPHS2-related SRNS, 9 carried the nonneutral p.Arg229Gln (commonly referred to as p.R229Q) polymorphism. Two additional subjects were homozygous for the p.R229Q polymorphism; SRNS in these cases was not considered to be caused by this common podocin variant. p.R229Q carriership did not affect age at disease onset or histology in this adolescent cohort; however, proteinuria at disease onset was significantly less marked in p.R229Q carriers than in patients with other mutations (3.5 vs. 6.4g/m2/day; P=0.03). The 5-year kidney survival was 64% in compound heterozygous patients carrying the p.R229Q polymorphism versus 23% for patients without the polymorphism (P=0.07). WT1 mutations were found in 4.1% (7/169) of the sporadic cases (including the previously diagnosed syndromic case of WT1 nephropathy with ambiguous genitalia). The patients encompassed a wide spectrum of clinical features, including Frasier syndrome, Wilms' tumor survivors, and isolated SRNS (Table 1). Three patients diagnosed with Wilms' tumor at infant age gradually developed mild proteinuria that, more than 10 years after cancer diagnosis, progressed to overt nephrotic syndrome and eventual diagnosis of the WT1 mutation. One of them required extended genetic testing of the entire WT1 gene in order to find the mutation p.(Arg355*) lying outside of the generally acknowledged hot spot for nephrotic syndrome-related mutations, but still within the region associated with simplex Wilms' tumor. Within the sporadic SRNS cohort, the WT1 cases did not differ from the NPHS2-related cases and those without detectable genetic abnormalities with respect to age at first manifestation, histopathology, and prospective renal survival. However, proteinuria at the time of diagnosis was significantly higher in WT1 cases (5.7 vs. 3.4g/m2/day; P=0.04). No known mutations in INF2 were detected in the sporadic SRNS; however, three novel sequence variants were found in heterozygous state: two nonsynonymous single-nucleotide substitutions (p.(Ile685Val) and p.(Arg877Gln)), and one intronic putative splice site mutation (c.1736-6C>T) (Table 2). The variant carriers did not differ from the remaining screened cohort with respect to age at disease onset, clinical manifestation, response to drugs, time to end-stage renal disease, and histopathology. Because of insufficient structural data, it was difficult to speculate on a potential effect of the detected novel missense variants on the structure and function of the INF2 protein (Table 4; Supplementary Material S2 online). Although p.(Ile685Val) lies in a region of high homology (90% similarity across chordates), it is a moderately evolutionarily conserved residue. The residue 877 is even less conserved, with only 12/25 orthologs expressing arginine; besides, the similarity rate among the orthologs for this fragment of the protein does not exceed 50%. Both variants lie within the formin homology 2 domain. A three-dimensional model based on the crystal structure of its closest homolog, that is, mDia mouse protein, was used to evaluate the probability of the variants to affect protein structure.13.Otomo T. Tomchik D.R. Otomo C. et al.Crystal structure of formin mDia in autoinhibited conformation.PLoS One. 2010; 5: e12896Crossref PubMed Scopus (34) Google Scholar The exchanges were found unlikely to disturb the helical structure or to change its hydrophobicity profile sufficiently to cause displacement. Besides, no effect of the mutations on mRNA splicing was observed (Supplementary Material S2 online).Table 4Summary of bioinformatic analyses of the detected novel sequence variantsNovel variantProtein changeProtein domainConservationMAFaMAF estimation based on data of 2168 individual genomes cataloged by 1000 Genomes Project and 12,101 individuals collected at NHLBI Exome Sequencing Project (accessed 13 December 2012).Human splicing finder36.Desmet F.O. Hamroun D. Lalande M. et al.Human Splicing Finder: an online bioinformatics tool to predict splicing signals.Nucleic Acids Res. 2009; 37: e67Crossref PubMed Scopus (1913) Google ScholarESE finder37.Cartegni L. Wang J. Zhu Z. et al.ESEfinder: a web resource to identify exonic splicing enhancers.Nucleic Acids Res. 2003; 31: 3568-3571Crossref PubMed Scopus (1266) Google ScholarPolyPhen32.Adzhubei I.A. Schmidt S. Peshkin L. et al.A method and a server for predicting damaging missense mutations.Nat Methods. 2010; 7: 248-249Crossref PubMed Scopus (9284) Google ScholarSIFT 33.Kumar P. Henikoff S. Ng P.C. Predicting the effect of coding non-synonymous variants on protein function using the SIFT algorithm.Nat Protoc. 2009; 4: 1073-1081Crossref PubMed Scopus (5005) Google ScholarPrevalence in control populationNPHS2 c.928G>Ap.(Glu310Lys)StomatinHighNot reportedNew biding site for 9G8, Tra2β enhancer proteins new site for hnRNP A1 bindingSF2/ASF binding site brokenProbably damagingTolerated0 c.451+3A>T———Not reportedBinding site for Tra2β enhancer protein broken New binding site for IIE silencer proteinNew sites for SC35, SRp40, and SRp55 binding——0WT1 c.1063A>Tp.(Arg355aMAF estimation based on data of 2168 individual genomes cataloged by 1000 Genomes Project and 12,101 individuals collected at NHLBI Exome Sequencing Project (accessed 13 December 2012).)N-terminalModerateNot reportedExonic enhancer sites (EIE, ESE) brokenNew site for SRp55 binding——0INF2 c.1736-6C>T———Not ReportedNo significant motif modificationsSF2/ASF and SRp40 binding site modification——0 c.2053A>Gp.(Ile685Val)FH2High Ap.(Arg877Gln)FH2Low1.5%New site for hnRNP A1 bindingSRp40 binding site modificationUnknownTolerated1%Abbreviations: EIE, exon-identity element; ESE, exonic splicing enhancer; FH2, formin homology 2; hnRNP, heterogeneous nuclear ribonucleoprotein; IIE, intron-identity element; MAF, minor allele frequency; NHLBI, National Heart, Lung, and Blood Institute; SF2/ASF, splicing factor 2/alternative splicing factor.a MAF estimation based on data of 2168 individual genomes cataloged by 1000 Genomes Project and 12,101 individuals collected at NHLBI Exome Sequencing Project (accessed 13 December 2012). Open table in a new tab Download .pdf (.75 MB) Help with pdf files Supplementary Material 2 Abbreviations: EIE, exon-identity element; ESE, exonic splicing enhancer; FH2, formin homology 2; hnRNP, heterogeneous nuclear ribonucleoprotein; IIE, intron-identity element; MAF, minor allele frequency; NHLBI, National Heart, Lung, and Blood Institute; SF2/ASF, splicing factor 2/alternative splicing factor. The compilation of a large unselected series of consecutive sporadic and familial cases of juvenile-onset SRNS in the international PodoNet registry allowed us to assess the prevalence of genetic abnormalities in known disease-causing genes in this age group. Whereas most previous genetic studies in patients with adolescent disease onset focused on individual SRNS-associated genes, we tested a panel of genes in order to establish a rational screening paradigm for genetic testing in this age group. NPHS2,5.Tsukaguchi H. Sudhakar A. Le T.C. et al.NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.J Clin Invest. 2002; 110: 1659-1666Crossref PubMed Scopus (223) Google Scholar, 6.Machuca E. Hummel A. Nevo F. et al.Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant.Kidney Int. 2009; 75: 727-735Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 14.Santín S. Tazón-Vega B. Silva I. et al.Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome.Clin J Am Soc Nephrol. 2011; 6: 344-354Crossref PubMed Scopus (68) Google Scholar WT1,7.Aucella F. Bisceglia L. De Bonis P. et al.WT1 mutations in nephrotic syndrome revisited. High prevalence in young girls, associations and renal phenotypes.Pediatr Nephrol. 2006; 21: 1393-1398Crossref PubMed Scopus (48) Google Scholar,15.Chernin G. Vega-Warner V. Schoeb D.S. et al.Genotype/phenotype correlation in nephrotic syndrome caused by WT1 mutations.Clin J Am Soc Nephrol. 2010; 5: 1655-1662Crossref PubMed Scopus (78) Google Scholar TRCP6,8.Heeringa S.F. Möller C.C. Du J. Yue L. et al.A novel TRPC6 mutation that causes childhood FSGS.PLoS One. 2009; 4: e7771Crossref PubMed Scopus (128) Google Scholar ACTN4,9.Kaplan J.M. Kim S.H. North K.N. et al.Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.Nat Genet. 2000; 24: 251-256Crossref PubMed Scopus (1040) Google Scholar and INF210.Brown E.J. Schlöndorff J.S. Becker D.J. et al.Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis.Nat Genet. 2010; 42: 72-76Crossref PubMed Scopus (340) Google Scholar were chosen as the genes considered most relevant in adolescent-onset disease. For recessive familial traits and sporadic cases, certain mutations in NPHS2 have been associated with late disease onset.6.Machuca E. Hummel A. Nevo F. et al.Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant.Kidney Int. 2009; 75: 727-735Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 14.Santín S. Tazón-Vega B. Silva I. et al.Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome.Clin J Am Soc Nephrol. 2011; 6: 344-354Crossref PubMed Scopus (68) Google Scholar, 16.Büscher A.K. Konrad M. Nagel M. et al.Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients.Clin Nephrol. 2012; 78: 47-53Crossref PubMed Scopus (51) Google Scholar, 17.Caridi G. Bertelli R. Scolari F. et al.Podocin mutations in sporadic focal-segmental glomerulosclerosis occurring in adulthood.Kidney Int. 2003; 64: 365Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 18.He N. Zahirieh A. Mei Y. et al.Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2007; 2: 31-37Crossref PubMed Scopus (62) Google Scholar, 19.McKenzie L.M. Hendrickson S.L. Briggs W.A. et al.NPHS2 variation in sporadic focal segmental glomerulosclerosis.J Am Soc Nephrol. 2007; 18: 2987-2995Crossref PubMed Scopus (57) Google Scholar The podocyte genes with AD transmission are generally characterized by a milder disease course with typically late disease onset, and may also occur sporadically due to de novo mutations.15.Chernin G. Vega-Warner V. Schoeb D.S. et al.Genotype/phenotype correlation in nephrotic syndrome caused by WT1 mutations.Clin J Am Soc Nephrol. 2010; 5: 1655-1662Crossref PubMed Scopus (78) Google Scholar, 20.Gigante M. Caridi G. Montemurno E. et al.TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype.Clin J Am Soc Nephrol. 2011; 6: 1626-1634Crossref PubMed Scopus (75) Google Scholar, 21.Weins A. Kenlan P. Herbert S. et al.Mutational and biological analysis of alpha-actinin-4 in focal segmental glomerulosclerosis.J Am Soc Nephrol. 2005; 16: 3694-3701Crossref PubMed Scopus (141) Google Scholar, 22.Boyer O. Benoit G. Gribouval O. et al.Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis.J Am Soc Nephrol. 2011; 22: 239-245Crossref PubMed Scopus (129) Google Scholar, 23.Barua M. Brown E.J. Charoonratana V.T. et al.Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis.Kidney Int. 2013; 83: 316-322Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar As previous works suggested a very low (<5%) incidence of TRPC6 and ACTN4 in sporadic SRNS cohorts,20.Gigante M. Caridi G. Montemurno E. et al.TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype.Clin J Am Soc Nephrol. 2011; 6: 1626-1634Crossref PubMed Scopus (75) Google Scholar,21.Weins A. Kenlan P. Herbert S. et al.Mutational and biological analysis of alpha-actinin-4 in focal segmental glomerulosclerosis.J Am Soc Nephrol. 2005; 16: 3694-3701Crossref PubMed Scopus (141) Google Scholar we restricted screening of these genes to familial cases. However, we explored the entire sporadic disease cohort for WT1 mutations and assessed the full coding sequence of INF2 in a randomly chosen subset of the sporadic cohort. In our cohort, 79% of cases occurred sporadically, 17% showed AR, and 4% AD inheritance. A genetic cause was identified in 30% of the AD, 13% of the AR, and 10% of the sporadic cases. Taken together, the overall mutation detection rate was 11%. This figure is in keeping with previous screening studies in SRNS patients suggesting a steep inverse relationship of the rate of genetic diagnoses with age. Reported prevalence figures of genetic causes were 81–100% for congenital nephrotic syndrome1.Machuca E. Benoit G. Nevo F. et al.Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome.J Am Soc Nephrol. 2010; 21: 1209-1217Crossref PubMed Scopus (113) Google Scholar, 2.Hinkes B.G. Mucha B. Vlangos C.N. et al.Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).Pediatrics. 2007; 119: e907-e919Crossref PubMed Scopus (357) Google Scholar, 4.Santín S. Bullich G. Tazón-Vega B. et al.Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome.Clin J Am Soc Nephrol. 2011; 6: 1139-1148Crossref PubMed Scopus (173) Google
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