Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia

Lipska‐Ziętkiewicz, Beata S.; Gellermann, Jutta; Boyer, Olivia; Ziętkiewicz, Szymon; Kari, Jameela A.; Shalaby, Mohamed; Özaltın, Fatih; Dušek, Jiří; Melk, Anette; Bayazıt, Aysun Karabay; Massella, Laura; Hyla-Klekot, Lidia; Habbig, Sandra; Godron, A.; Szczepańska, Maria; Bieniaś, Beata; Drożdż, Dorota; Odeh, Rasha; Jarmużek, Wioletta; Zachwieja, Katarzyna; Trautmann, Agnes; Antignac, Corinne; Schaefer, Franz

doi:10.1371/journal.pone.0180926

Cited by 31 publications

(33 citation statements)

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“…All statistical analyses of the reported individual studies of the PodoNet registry were performed using SAS® Version 9.4 (Cary, USA). Statistical details can be obtained from the original articles ( 1 – 5 ).…”

Section: Podonet Study Cohort: Methods and Definitionsmentioning

confidence: 99%

“…The PodoNet consortium analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 PodoNet patients from 28 families—the largest SMARCAL1 -associated nephropathy cohort to date ( 5 ). The diagnosis of SMARCAL1 -associated disease was made either by the presence of typical syndromic feature or unexpectedly by NGS panel screening (11/34 children).…”

Section: Clinical and Genetic Spectrum Of The Podonet Cohort Study—rementioning

confidence: 99%

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Exploring the Clinical and Genetic Spectrum of Steroid Resistant Nephrotic Syndrome: The PodoNet Registry

2018

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Background: Steroid resistant nephrotic syndrome (SRNS) is a rare condition, accounting for 10–15% of all children with idiopathic nephrotic syndrome. SRNS can be caused by genetic abnormalities or immune system dysfunction. The prognosis of SRNS varies from permanent remission to progression to end-stage kidney disease, and post-transplant recurrence is common.Objectives: The PodoNet registry project aims to explore the demographics and phenotypes of immune-mediated and genetic forms of childhood SRNS, to assess genotype-phenotype correlations, to evaluate clinical management and long-term outcomes, and to search for novel genetic entities and diagnostic and prognostic biomarkers in SRNS.Methods: In 2009, an international registry for SRNS was established to collect retro- and prospective information on renal and extrarenal disease manifestations, histopathological and genetic findings and information on family history, pharmacotherapy responsiveness and long-term outcomes. To date, more than 2,000 patients have been enrolled at 72 pediatric nephrology centers, constituting the largest pediatric SRNS cohort assembled to date.Results: In the course of the project, traditional Sanger sequencing was replaced by NGS-based gene panel screening covering over 30 podocyte-related genes complemented by whole exome sequencing. These approaches allowed to establish genetic diagnoses in 24% of the patients screened, widened the spectrum of genetic disease entities presenting with SRNS phenotype (COL4A3-5, CLCN5), and contributed to the discovery of new disease causing genes (MYOE1, PTPRO). Forty two percent of patients responded to intensified immunosuppression with complete or partial remission of proteinuria, whereas 58% turned out multi-drug resistant. Medication responsiveness was highly predictive of a favorable long-term outcome, whereas the diagnosis of genetic disease was associated with a high risk to develop end-stage renal disease during childhood. Genetic SRNS forms were generally resistant to immunosuppressive treatment, justifying to avoid such pharmacotherapies altogether once a genetic diagnosis is established. Even symptomatic anti-proteinuric treatment with RAS antagonists seems to be challenging and of limited efficacy in genetic forms of SRNS. The risk of post-transplant disease recurrence was around 30% in non-genetic SRNS whereas it is negligible in genetic cases.Conclusion: In summary, the PodoNet Registry has collected detailed clinical and genetic information in a large SRNS cohort and continues to generate fundamental insights regarding demographic and etiological disease aspects, genotype-phenotype associations, the efficacy of therapeutic strategies, and long-term patient and renal outcomes including post-transplant disease recurrence.

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Section: Podonet Study Cohort: Methods and Definitionsmentioning

confidence: 99%

Section: Clinical and Genetic Spectrum Of The Podonet Cohort Study—rementioning

confidence: 99%

Exploring the Clinical and Genetic Spectrum of Steroid Resistant Nephrotic Syndrome: The PodoNet Registry

2018

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“…This missense change, mapping in a run of homozygosity (ROH) of about 5 Mb, involved a highly-conserved residue; it was classified as likely pathogenic by Varsome ( ), according to the American College of Medical Genetics (ACMG) guidelines [ 18 ], and it had been previously reported in two patients with clinically-diagnosed Schimke immuno-osseous dysplasia (SIOD), in a compound heterozygous state with another variant (c.3G>A, p.Met1Ile) in one case [ 19 ] and in a homozygous state in the other one [ 20 , 21 ] ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…A similar mild form of SIOD was described in a patient with a different homozygous change at the same residue (p.Arg561Cys). Severe clinical manifestations were reported in a boy carrying the p.Arg561His variant in the compound heterozygous state with the c.3G>A (p.Met1Ile) change, causing a start loss and generating a predicted truncated protein missing the nuclear location signal [ 20 ]. Clinical features of SIOD patients with variants involving the Arg561 residue are summarized in Table 1 .…”

Section: Discussionmentioning

confidence: 99%

Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells

Bertulli

Antonio

Doria

et al. 2020

IJMS

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Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype–genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD—both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.

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“…Depending on their tissue specificity and type of mutation, transcription factor variants can cause a range of phenotypes from largely kidney-limited disease to severe syndromic disorders. 5,6 Recently, evidence has emerged that nuclear dysfunction in SRNS is not limited to transcription factor abnormalities. Mutations in nuclear pore complex (NPC) proteins (ie, NUPs) have been demonstrated to cause human proteinuric disease.…”

mentioning

confidence: 99%

NUP Nephropathy: When Defective Pores Cause Leaky Glomeruli

Lipska‐Ziętkiewicz

Schaefer

2019

American Journal of Kidney Diseases

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Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia

Cited by 31 publications

References 14 publications

Exploring the Clinical and Genetic Spectrum of Steroid Resistant Nephrotic Syndrome: The PodoNet Registry

Exploring the Clinical and Genetic Spectrum of Steroid Resistant Nephrotic Syndrome: The PodoNet Registry

Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells

NUP Nephropathy: When Defective Pores Cause Leaky Glomeruli

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