WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

Página do item simplificado
dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorFERRARI, M. T. M.
dc.contributor.authorWATANABE, A.
dc.contributor.authorSILVA, T. E. Da
dc.contributor.authorGOMES, N. L.
dc.contributor.authorBATISTA, R. L.
dc.contributor.authorNISHI, M. Y.
dc.contributor.authorPAULA, L. C. P. De
dc.contributor.authorCOSTA, E. C.
dc.contributor.authorCOSTA, E. M. F.
dc.contributor.authorCUKIER, P.
dc.contributor.authorONUCHIC, L. F.
dc.contributor.authorMENDONCA, B. B.
dc.contributor.authorDOMENICE, S.
dc.date.accessioned2024-03-13T19:52:10Z
dc.date.available2024-03-13T19:52:10Z
dc.date.issued2022
dc.description.abstractWilms' tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms' tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs∗14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.eng
dc.description.indexMEDLINE
dc.description.indexPubMed
dc.description.indexScopus
dc.description.indexDimensions
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP, (2014/50,137-5)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq, (305743/2011-2, 308873/2018-1)
dc.identifier.citationSEXUAL DEVELOPMENT, v.16, n.1, p.46-54, 2022
dc.identifier.doi10.1159/000517373
dc.identifier.issn1661-5425
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/58605
dc.language.isoeng
dc.publisherS. KARGER AGeng
dc.relation.ispartofSexual Development
dc.rightsrestrictedAccesseng
dc.rights.holderCopyright S. KARGER AGeng
dc.subject46,XX testicular/ovarian-testicular DSDeng
dc.subjectDenys-Drash syndromeeng
dc.subjectFrasier syndromeeng
dc.subjectPrimary ovarian insufficiencyeng
dc.subjectRenal failureeng
dc.subjectWilms' tumor 1 (WT1) geneeng
dc.subject.otherfemaleeng
dc.subject.otherhumanseng
dc.subject.otherkidney neoplasmseng
dc.subject.othermaleeng
dc.subject.othermutationeng
dc.subject.otherphenotypeeng
dc.subject.othersexual developmenteng
dc.subject.otherwilms tumoreng
dc.subject.otherwt1 proteinseng
dc.subject.otherwt1 proteineng
dc.subject.otherwt1 protein, humaneng
dc.subject.otherfemaleeng
dc.subject.othergeneticseng
dc.subject.otherhumaneng
dc.subject.otherkidney tumoreng
dc.subject.othermaleeng
dc.subject.othermutationeng
dc.subject.othernephroblastomaeng
dc.subject.otherphenotypeeng
dc.subject.othersexual developmenteng
dc.titleWT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Diseaseeng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.author.externalSILVA, T. E. Da:Unidade de Endocrinologia Do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
hcfmusp.author.externalPAULA, L. C. P. De:Unidade de Desordens Do Desenvolvimento Sexual, UFRGS, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
hcfmusp.author.externalCOSTA, E. C.:Unidade de Desordens Do Desenvolvimento Sexual, UFRGS, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
hcfmusp.citation.scopus7
hcfmusp.contributor.author-fmusphcMARIA TEREZA MARTINS FERRARI
hcfmusp.contributor.author-fmusphcANDREIA WATANABE
hcfmusp.contributor.author-fmusphcNATHALIA LISBOA ROSA ALMEIDA GOMES
hcfmusp.contributor.author-fmusphcRAFAEL LOCH BATISTA
hcfmusp.contributor.author-fmusphcMIRIAN YUMIE NISHI
hcfmusp.contributor.author-fmusphcELAINE MARIA FRADE COSTA
hcfmusp.contributor.author-fmusphcPRISCILLA CUKIER
hcfmusp.contributor.author-fmusphcLUIZ FERNANDO ONUCHIC
hcfmusp.contributor.author-fmusphcBERENICE BILHARINHO DE MENDONCA
hcfmusp.contributor.author-fmusphcSORAHIA DOMENICE
hcfmusp.description.beginpage46
hcfmusp.description.endpage54
hcfmusp.description.issue1
hcfmusp.description.volume16
hcfmusp.origemSCOPUS
hcfmusp.origem.dimensionspub.1140413044
hcfmusp.origem.pubmed34392242
hcfmusp.origem.scopus2-s2.0-85113955773
hcfmusp.relation.referenceAhmed S.F., Khwaja O., Hughes I.A., The role of a clinical score in the assessment of ambiguous genitalia, BJU Int., 85, 1, pp. 120-124, (2000)eng
hcfmusp.relation.referenceAhn Y.H., Park E.J., Kang H.G., Kim S.H., Cho H.Y., Shin J.I., Et al., Genotype-phenotype analysis of pediatric patients with WT1 glomerulopathy, Pediatr Nephrol., 32, 1, pp. 81-89, (2017)eng
hcfmusp.relation.referenceAmbu R., Vinci L., Gerosa C., Fanni D., Obinu E., Faa A., Et al., WT1 expression in the human fetus during development, Eur J Histochem., 59, 2, (2015)eng
hcfmusp.relation.referenceAuton A., Auton A., Brooks L.D., Durbin R.M., Garrison E.P., Kang H.M., Et al., A global reference for human genetic variation, Nature., 526, 7571, pp. 68-74, (2015)eng
hcfmusp.relation.referenceBarbaux S., Niaudet P., Gubler M.C., Grunfeld J.P., Jaubert F., Kuttenn F., Et al., Donor splice-site mutations in WT1 are responsible for Frasier syndrome, Nat Genet., 17, 4, pp. 467-470, (1997)eng
hcfmusp.relation.referenceBreslow N.E., Collins A.J., Ritchey M.L., Grigoriev Y.A., Peterson S.M., Green D.M., End stage renal disease in patients with Wilms tumor: Results from the National Wilms Tumor Study Group and the United States Renal Data System, J Urol., 174, 5, pp. 1972-1975, (2005)eng
hcfmusp.relation.referenceBrownstein C.A., Beggs A.H., Homer N., Merriman B., Yu T.W., Flannery K.C., Et al., An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge, Genome Biol., 15, 3, (2014)eng
hcfmusp.relation.referenceCall K.M., Glaser T., Ito C.Y., Buckler A.J., Pelletier J., Haber D.A., Et al., Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus, Cell., 60, 3, pp. 509-520, (1990)eng
hcfmusp.relation.referenceCen C., Chen M., Zhou J., Zhang L., Duo S., Jiang L., Et al., Inactivation of Wt1 causes pre-granulosa cell to steroidogenic cell transformation and defect of ovary development, Biol Reprod., 103, 1, pp. 60-69, (2020)eng
hcfmusp.relation.referenceChernin G., Vega-Warner V., Schoeb D.S., Heeringa S.F., Ovunc B., Saisawat P., Et al., Genotype/ phenotype correlation in nephrotic syndrome caused by WT1 mutations, Clin J Am Soc Nephrol., 5, 9, pp. 1655-1662, (2010)eng
hcfmusp.relation.referenceDa Silva T.E., Nishi M.Y., Costa E.M., Martin R.M., Carvalho F.M., Mendonca B.B., Et al., A novel WT1 heterozygous nonsense mutation (p. K248X) causing a mild and slightly progressive nephropathy in a 46, XY patient with Denys-Drash syndrome, Pediatr Nephrol., 26, 8, pp. 1311-1315, (2011)eng
hcfmusp.relation.referenceDa Silva T.E., Gomes N.L., Lerario A.M., Keegan C.E., Nishi M.Y., Carvalho F.M., Et al., Genetic evidence of the association of DEAH-Box helicase 37 defects with 46, XY gonadal dysgenesis spectrum, J Clin Endocrinol Metab., 104, 12, pp. 5923-5934, (2019)eng
hcfmusp.relation.referenceDenys P., Malvaux P., Van Den Berghe H., Tanghe W., Proesmans W., [Association of an anatomo-pathological syndrome of Male pseudohermaphroditism, Wilms' tumor, parenchymatous nephropathy and XX/XY mosaicism], Arch Fr Pediatr., 24, 7, pp. 729-739, (1967)eng
hcfmusp.relation.referenceDrash A., Sherman F., Hartmann W.H., Blizzard R.M., A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal disease, J Pediatr., 76, 4, pp. 585-593, (1970)eng
hcfmusp.relation.referenceEozenou C., Elaidy A., McElreavey K., Mutation in WT1 (Wilms' Tumor Suppressor 1) Associated with 46, XX Testicular DSD, Washington, DC: International Meeting of Pediatric Endocrinology, (2017)eng
hcfmusp.relation.referenceEozenou C., Gonen N., Touzon M.S., Jorgensen A., Yatsenko S.A., Fusee L., Et al., Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene, Proc Natl Acad Sci USA., 117, 24, pp. 13680-13688, (2020)eng
hcfmusp.relation.referenceEzaki J., Hashimoto K., Asano T., Kanda S., Akioka Y., Hattori M., Et al., Gonadal tumor in Frasier syndrome: A review and classification, Cancer Prev Res (Phila)., 8, 4, pp. 271-276, (2015)eng
hcfmusp.relation.referenceFerrari M.T.M., Batista R.L., Mendonca B.B., Domenice S., WT1 pathogenic variants are associated with a broad spectrum of differences in sex development phenotypes and heterogeneous progression of renal disease, Figshareeng
hcfmusp.relation.referenceFranca M.M., Funari M.F.A., Nishi M.Y., Narcizo A.M., Domenice S., Costa E.M.F., Et al., Identification of the first homozygous 1-bp deletion in GDF9 gene leading to primary ovarian insufficiency by using targeted massively parallel sequencing, Clin Genet., 93, pp. 408-411, (2018)eng
hcfmusp.relation.referenceFrasier S.D., Bashore R.A., Mosier H.D., Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins, J Pediatr., 64, pp. 740-745, (1964)eng
hcfmusp.relation.referenceFunari M.F.A., De Barros J.S., Santana L.S., Lerario A.M., Freire B.L., Homma T.K., Et al., Evaluation of SHOX defects in the era of next-generation sequencing, Clin Genet., 96, 3, pp. 261-265, (2019)eng
hcfmusp.relation.referenceGao F., Zhang J., Wang X., Yang J., Chen D., Huff V., Et al., Wt1 functions in ovarian follicle development by regulating granulosa cell differentiation, Hum Mol Genet., 23, 2, pp. 333-341, (2014)eng
hcfmusp.relation.referenceGessler M., Poustka A., Cavenee W., Neve R.L., Orkin S.H., Bruns G.A., Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping, Nature., 343, 6260, pp. 774-778, (1990)eng
hcfmusp.relation.referenceGomes N.L., De Paula L.C.P., Silva J.M., Silva T.E., Lerario A.M., Nishi M.Y., Et al., A 46, XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant, Clin Genet., 95, 1, pp. 172-176, (2019)eng
hcfmusp.relation.referenceGuaragna M.S., Lutaif A.C., Bittencourt V.B., Piveta C.S., Soardi F.C., Castro L.C., Et al., Frasier syndrome: Four new cases with unusual presentations, Arq Bras Endocrinol Metabol., 56, 8, pp. 525-532, (2012)eng
hcfmusp.relation.referenceGuaragna M.S., Ribeiro De Andrade J.G., De Freitas Carli B., Belangero V.M., Maciel-Guerra A.T., Guerra-Junior G., Et al., WT1 haploinsufficiency supports milder renal manifestation in two patients with Denys-Drash syndrome, Sex Dev., 11, 1, pp. 34-39, (2017)eng
hcfmusp.relation.referenceHaber D.A., Sohn R.L., Buckler A.J., Pelletier J., Call K.M., Housman D.E., Alternative splicing and genomic structure of the Wilms tumor gene WT1, Proc Natl Acad Sci USA., 88, 21, pp. 9618-9622, (1991)eng
hcfmusp.relation.referenceHersmus R., Van Der Zwan Y.G., Stoop H., Bernard P., Sreenivasan R., Oosterhuis J.W., Et al., A 46, XY female DSD patient with bilateral gonadoblastoma, a novel SRY missense mutation combined with a WT1 KTS splice-site mutation, PLoS One., 7, 7, (2012)eng
hcfmusp.relation.referenceHoefele J., Kemper M.J., Schoenermarck U., Mueller S., Klein H.G., Lemke A., Truncating Wilms tumor suppressor gene 1 mutation in an XX female with adult-onset focal segmental glomerulosclerosis and streak ovaries: A case report, Nephron., 135, 1, pp. 72-76, (2017)eng
hcfmusp.relation.referenceHohenstein P., Hastie N.D., The many facets of the Wilms' tumour gene, WT1, Hum Mol Genet, pp. R196-R201, (2006)eng
hcfmusp.relation.referenceHossain A., Saunders G.F., The human sex-determining gene SRY is a direct target of WT1, J Biol Chem., 276, 20, pp. 16817-16823, (2001)eng
hcfmusp.relation.referenceHughes I.A., Houk C., Ahmed S.F., Lee P.A., Consensus statement on management of intersex disorders, J Pediatr Urol., 2, 3, pp. 148-162, (2006)eng
hcfmusp.relation.referenceIsmaili K., Verdure V., Vandenhoute K., Janssen F., Hall M., WT1 gene mutations in three girls with nephrotic syndrome, Eur J Pediatr., 167, 5, pp. 579-581, (2008)eng
hcfmusp.relation.referenceJoki-Erkkila M.M., Karikoski R., Rantala I., Lenko H.-L., Visakorp T., Heinonen P., Gonadoblastoma and dysgerminoma associated with XY gonadal dysgenesis in an adolescent with chronic renal failure: A case of Frasier syndrome, J Pediatr Adolesc Gynecol., 15, pp. 145-149, (2002)eng
hcfmusp.relation.referenceKilleen O.G., Kelehan P., Reardon W., Double vagina with sex reversal, congenital diaphragmatic hernia, pulmonary and cardiac malformations-another case of Meacham syndrome, Clin Dysmorphol., 11, 1, pp. 25-28, (2002)eng
hcfmusp.relation.referenceKlamt B., Koziell A., Poulat F., Wieacker P., Scambler P., Berta P., Et al., Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms, Hum Mol Genet., 7, 4, pp. 709-714, (1998)eng
hcfmusp.relation.referenceKoziell A., Grundy R., Frasier and Denys-Drash syndromes: Different disorders or part of a spectrum?, Arch Dis Child., 81, 4, pp. 365-369, (1999)eng
hcfmusp.relation.referenceLehnhardt A., Karnatz C., Ahlenstiel-Grunow T., Benz K., Benz M.R., Budde K., Et al., Clinical and molecular characterization of patients with heterozygous mutations in Wilms tumor suppressor gene 1, Clin J Am Soc Nephrol., 10, 5, pp. 825-831, (2015)eng
hcfmusp.relation.referenceLipska B.S., Ranchin B., Iatropoulos P., Gellermann J., Melk A., Ozaltin F., Et al., Genotype-phenotype associations in WT1 glomerulopathy, Kidney Int., 85, 5, pp. 1169-1178, (2014)eng
hcfmusp.relation.referenceMaaswinkel-Mooij P.D., Stokvis-Brantsma W.H., Phenotypically normal girl with Male pseudohermaphroditism, hypoplastic left ventricle, lung aplasia, horseshoe kidney, and diaphragmatic hernia, Am J Med Genet., 42, 5, pp. 647-648, (1992)eng
hcfmusp.relation.referenceMeacham L.R., Winn K.J., Culler F.L., Parks J.S., Double vagina, cardiac, pulmonary, and other genital malformations with 46, XY karyotype, Am J Med Genet., 41, 4, pp. 478-481, (1991)eng
hcfmusp.relation.referenceMelo K.F., Martin R.M., Costa E.M., Carvalho F.M., Jorge A.A., Arnhold I.J., Et al., An unusual phenotype of Frasier syndrome due to IVS9+4C> T mutation in the WT1 gene: Predominantly Male ambiguous genitalia and absence of gonadal dysgenesis, J Clin Endocrinol Metab., 87, 6, pp. 2500-2505, (2002)eng
hcfmusp.relation.referenceMiller S.A., Dykes D.D., Polesky H.F., A simple salting out procedure for extracting DNA from human nucleated cells, Nucleic Acids Res., 16, 3, (1988)eng
hcfmusp.relation.referenceNaslavsky M.S., Yamamoto G.L., De Almeida T.F., Ezquina S.A.M., Sunaga D.Y., Pho N., Et al., Exomic variants of an elderly cohort of Brazilians in the ABraOM database, Hum Mutat., 38, 7, pp. 751-763, (2017)eng
hcfmusp.relation.referencePatek C.E., Little M.H., Fleming S., Miles C., Charlieu J.P., Clarke A.R., Et al., A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome, Proc Natl Acad Sci USA., 96, 6, pp. 2931-2936, (1999)eng
hcfmusp.relation.referencePelletier J., Bruening W., Kashtan C.E., Mauer S.M., Manivel J.C., Striegel J.E., Et al., Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome, Cell., 67, 2, pp. 437-447, (1991)eng
hcfmusp.relation.referencePritchard-Jones K., Fleming S., Davidson D., Bickmore W., Porteous D., Gosden C., Et al., The candidate Wilms' tumour gene is involved in genitourinary development, Nature., 346, 6280, pp. 194-197, (1990)eng
hcfmusp.relation.referenceRichards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Et al., Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, Genet Med., 17, 5, pp. 405-424, (2015)eng
hcfmusp.relation.referenceRose E.A., Glaser T., Jones C., Smith C.L., Lewis W.H., Call K.M., Et al., Complete physical map of the WAGR region of 11p13 localizes a candidate Wilms' tumor gene, Cell., 60, 3, pp. 495-508, (1990)eng
hcfmusp.relation.referenceSuri M., Kelehan P., O'Neill D., Vadeyar S., Grant J., Ahmed S.F., Et al., WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations, Am J Med Genet A., 143 A, 19, pp. 2312-2320, (2007)eng
hcfmusp.relation.referenceWagner K.D., Wagner N., Schedl A., The complex life of WT1, J Cell Sci., 116, pp. 1653-1658, (2003)eng
hcfmusp.relation.referenceWagner K.D., Wagner N., Schley G., Theres H., Scholz H., The Wilms' tumor suppressor Wt1 encodes a transcriptional activator of the class IV POU-domain factor Pou4f2 (Brn-3b), Gene., 305, 2, pp. 217-223, (2003)eng
hcfmusp.relation.referenceWang H., Li G., Zhang J., Gao F., Li W., Qin Y., Et al., Novel WT1 missense mutations in Han Chinese women with premature ovarian failure, Sci Rep., 5, (2015)eng
hcfmusp.scopus.lastupdate2024-05-17
relation.isAuthorOfPublicationdb121a66-14b9-4562-a4ba-445af7b65550
relation.isAuthorOfPublication95d9eec4-72fb-4fb1-9673-84ae4d16c99b
relation.isAuthorOfPublication21593e5d-408c-48f3-9add-525627ba53b0
relation.isAuthorOfPublicationd062df7d-421a-4fad-81aa-6e17d34136dd
relation.isAuthorOfPublication8c0902a5-7ac0-4f77-b4e8-89dbf63647a5
relation.isAuthorOfPublicationc6928e0a-cd60-4e37-8aec-ccef17a1daa9
relation.isAuthorOfPublication82bdb676-faf5-4a27-8f5b-8ed8a9017afd
relation.isAuthorOfPublicationac7c3a85-ee5f-4d06-88c3-cc31c874dfa9
relation.isAuthorOfPublicationf9dd8bf5-173e-4843-93cd-66012ee0ef1b
relation.isAuthorOfPublication39dda9d1-49dc-46d1-8e72-f90305de46a3
relation.isAuthorOfPublication.latestForDiscoverydb121a66-14b9-4562-a4ba-445af7b65550
Arquivos
Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - HC/ICESP
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - HC/ICr
Artigos e Materiais de Revistas Científicas - HC/IPq
Artigos e Materiais de Revistas Científicas - LIM/29
Carregar mais