The KOUNCIL Consortium: From Genetic Defects to Therapeutic Development for Nephronophthisis

Renkema, Kirsten Y.; Giles, Rachel; Lilien, Marc R.; Beales, Philip L.; Roepman, Ronald; Oud, Machteld M.; Arts, Heleen H.; Knoers, Nine V A M

doi:10.3389/fped.2018.00131

Cited by 4 publications

(5 citation statements)

References 20 publications

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“…Any genetic testing should be done with appropriate pre-test counselling. Molecular confirmation of NPHP is possible in about 60% of affected individuals by identifying the pathogenic variants in the NPHP-associated genes [ 1 , 13 , 14 ]. Our patient was found to have an autosomal recessive inheritance of the NPHP3 gene with compound heterozygous variants: a pathogenic variant (p.E145Vfs*3) inherited from her father and a likely pathogenic variant (p.K144E) inherited from her mother.…”

Section: Discussionmentioning

confidence: 99%

“…There are about 25 known gene-disease associations with NPHP and most of these variants result in loss of function of the proteins [ 5 , 14 ]. Proteomic studies have revealed these proteins form macromolecular complexes known as nephrocystin modules, which work simultaneously to support cilio-genesis and ciliary function [ 5 , 14 ]. Nephrocystin 1 encoded by NPHP1 , is an adaptor protein found on primary cilia and renal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a Novel Compound Heterozygous Pathogenic Variant

Ajiboye,

Vengoechea,

Gupta

et al. 2023

Am J Case Rep

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Patient: Female, 19-year-old Final Diagnosis: Nephronophthisis Symptoms: Fatigue • poor appetite Clinical Procedure: — Specialty: Genetics • Nephrology Objective: Rare disease Background: Nephronophthisis, an autosomal recessive ciliopathy involving mutations in primary cilium genes, is characterized by chronic tubulointerstitial nephritis and a defective urine concentrating capacity. It accounts for about 5% of renal failure in children and adolescents and usually progresses to end-stage renal disease before the age of 30 years. Nephronophthisis is associated with extrarenal manifestations, including retinitis pigmentosa in Senior-Loken syndrome (SLS), and liver fibrosis in 10–20% of cases. While some presenting patterns could be characteristic, patients may have atypical presentation, making diagnosis difficult. Tubulointerstitial fibrosis is the predominant feature on histology and as such, diagnosis depends mostly on genetic testing. Despite advances in renal genomics over the years with a better understanding of primary cilia and ciliary theory, about 40% of nephronophthisis cases go undiagnosed. As the underlying genetic etiologies are not fully understood, morphologic pathologic findings are non-specific, and treatment options are limited to dialysis and transplantation. Case Report: We describe a unique case of a patient with adolescent nephronophthisis who presented with advanced chronic kidney disease and severe pancytopenia, who progressed to end-stage renal disease at the age of 19, and was found to have syndromic nephronophthisis with compound heterozygous inheritance. Conclusions: This report highlights the atypical presentation patterns that can be seen in syndromic nephronophthisis, the importance of genetic diagnosis when there is a high index of suspicion, and the need to further study genetic variants to better understand and diagnose the disease and to develop targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a Novel Compound Heterozygous Pathogenic Variant

Ajiboye,

Vengoechea,

Gupta

et al. 2023

Am J Case Rep

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“…Induced pluripotent stem cells (iPSCs) technology may be a powerful tool to facilitate personalized drug assessment as iPSCs can be derived from fluids and tissues that are easy to obtain (blood, fibroblasts and urine) and can subsequently be differentiated into cells of a relevant tissue. Thus, a personalized approach for drug screening and gene-based therapy may be the future direction for individuals diagnosed with Sensenbrenner syndrome [17,18].…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease

Walczak‐Sztulpa

Posmyk

Bukowska‐Olech

et al. 2020

Orphanet J Rare Dis

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Background: Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra-and interfamilial clinical variability has been reported in CED, which is consistent with CED's genetic heterogeneity and is indicative of genetic background effects. Results: Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. Conclusion: The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical-and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.

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“…Access to and cost of genetic testing is variable, in some countries being available only in research units [323], and often with significant turnaround time. Despite this, implementation of testing and registries has allowed the creation of comprehensive databases of genotype-phenotype correlation, which will help with future diagnosis [324]. Registries exist in the USA [56], China [325], Germany, Austria, and Denmark [318], and Holland [326].…”

Section: Diagnosis Screening and Preventionmentioning

confidence: 99%

Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease

Gupta

Ozimek-Kulik

Phillips

2021

Genes

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The exponential rise in our understanding of the aetiology and pathophysiology of genetic cystic kidney diseases can be attributed to the identification of cystogenic genes over the last three decades. The foundation of this was laid by positional cloning strategies which gradually shifted towards next-generation sequencing (NGS) based screenings. This shift has enabled the discovery of novel cystogenic genes at an accelerated pace unlike ever before and, most notably, the past decade has seen the largest increase in identification of the genes which cause nephronophthisis (NPHP). NPHP is a monogenic autosomal recessive cystic kidney disease caused by mutations in a diverse clade of over 26 identified genes and is the most common genetic cause of renal failure in children. NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations. This review provides a timely update on our knowledge of this disease, including epidemiology, pathophysiology, anatomical and molecular features. We delve into the diversity of the NPHP causing genes and discuss known molecular mechanisms and biochemical pathways that may have possible points of intersection with polycystic kidney disease (the most studied renal cystic pathology). We delineate the pathologies arising from extra-renal complications and co-morbidities and their impact on quality of life. Finally, we discuss the current diagnostic and therapeutic modalities available for disease management, outlining possible avenues of research to improve the prognosis for NPHP patients.

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The KOUNCIL Consortium: From Genetic Defects to Therapeutic Development for Nephronophthisis

Cited by 4 publications

References 20 publications

Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a Novel Compound Heterozygous Pathogenic Variant

Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a Novel Compound Heterozygous Pathogenic Variant

Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease

Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease

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