260 results on '"Nine V A M Knoers"'
Search Results
2. Wnt5a Deficiency Leads to Anomalies in Ureteric Tree Development, Tubular Epithelial Cell Organization and Basement Membrane Integrity Pointing to a Role in Kidney Collecting Duct Patterning.
- Author
-
Ilkka Pietilä, Renata Prunskaite-Hyyryläinen, Susanna Kaisto, Elisavet Tika, Albertien M van Eerde, Antti M Salo, Leonardo Garma, Ilkka Miinalainen, Wout F Feitz, Ernie M H F Bongers, André Juffer, Nine V A M Knoers, Kirsten Y Renkema, Johanna Myllyharju, and Seppo J Vainio
- Subjects
Medicine ,Science - Abstract
The Wnts can be considered as candidates for the Congenital Anomaly of Kidney and Urinary Tract, CAKUT diseases since they take part in the control of kidney organogenesis. Of them Wnt5a is expressed in ureteric bud (UB) and its deficiency leads to duplex collecting system (13/90) uni- or bilateral kidney agenesis (10/90), hypoplasia with altered pattern of ureteric tree organization (42/90) and lobularization defects with partly fused ureter trunks (25/90) unlike in controls. The UB had also notably less tips due to Wnt5a deficiency being at E15.5 306 and at E16.5 765 corresponding to 428 and 1022 in control (p
- Published
- 2016
- Full Text
- View/download PDF
3. Cas9-directed long-read sequencing to resolve optical genome mapping findings in leukemia diagnostics
- Author
-
Eddy N. de Boer, Vincent Vroom, Arjen J. Scheper, Lennart F. Johansson, Laura Bosscher, Nettie Rietema, Sabrina Z. Commandeur-Jan, Nine V. A. M. Knoers, Birgit Sikkema-Raddatz, Eva van den Berg, and Cleo C. van Diemen
- Subjects
Medicine ,Science - Abstract
Abstract Leukemias are genetically heterogeneous and diagnostics therefore includes various standard-of-care (SOC) techniques, including karyotyping, SNP-array and FISH. Optical genome mapping (OGM) may replace these as it detects different types of structural aberrations simultaneously and additionally detects much smaller aberrations (500 bp vs 5–10 Mb with karyotyping). However, its resolution may still be too low to define clinical relevance of aberrations when they are located between two OGM labels or when labels are not distinct enough. Here, we test the potential of Cas9-directed long-read sequencing (LRS) as an additional technique to resolve such potentially relevant new findings. From an internal Bionano implementation study we selected ten OGM calls that could not be validated with SOC methods. Per variant we designed crRNAs for Cas9 enrichment, prepared libraries and sequenced them on a MinION/GridION device. We could confirm all aberrations and, importantly, the actual breakpoints of the OGM calls were located between 0.2 and 5.5 kb of the OGM-estimated breakpoints, confirming the high reliability of OGM. Furthermore, we show examples of redefinition of aberrations between labels that enable judgment of clinical relevance. Our results suggest that Cas9-directed LRS can be a relevant and flexible secondary technique in diagnostic workflows including OGM.
- Published
- 2024
- Full Text
- View/download PDF
4. TRPC6 single nucleotide polymorphisms and progression of idiopathic membranous nephropathy.
- Author
-
Julia M Hofstra, Marieke J H Coenen, Mascha M V A P Schijvenaars, Jo H M Berden, Johan van der Vlag, Lies H Hoefsloot, Nine V A M Knoers, Jack F M Wetzels, and Tom Nijenhuis
- Subjects
Medicine ,Science - Abstract
Activating mutations in the Transient Receptor Potential channel C6 (TRPC6) cause autosomal dominant focal segmental glomerular sclerosis (FSGS). TRPC6 expression is upregulated in renal biopsies of patients with idiopathic membranous glomerulopathy (iMN) and animal models thereof. In iMN, disease progression is characterized by glomerulosclerosis. In addition, a context-dependent TRPC6 overexpression was recently suggested in complement-mediated podocyte injury in e.g. iMN. Hence, we hypothesized that genetic variants in TRPC6 might affect susceptibility to development or progression of iMN.Genomic DNA was isolated from blood samples of 101 iMN patients and 292 controls. By direct sequencing of the entire TRPC6 gene, 13 single nucleotide polymorphisms (SNPs) were identified in the iMN cohort, two of which were causing an amino acid substitution (rs3802829; Pro15Ser and rs36111323, Ala404Val). No statistically significant differences in genotypes or allele frequencies between patients and controls were observed. Clinical outcome in patients was determined (remission n = 26, renal failure n = 46, persistent proteinuria n = 29, follow-up median 80 months {range 51-166}). The 13 identified SNPs showed no association with remission or renal failure. There were no differences in genotypes or allele frequencies between patients in remission and progressors.Our data suggest that TRPC6 polymorphisms do not affect susceptibility to iMN, or clinical outcome in iMN.
- Published
- 2014
- Full Text
- View/download PDF
5. Genes in the ureteric budding pathway: association study on vesico-ureteral reflux patients.
- Author
-
Albertien M van Eerde, Karen Duran, Els van Riel, Carolien G F de Kovel, Bobby P C Koeleman, Nine V A M Knoers, Kirsten Y Renkema, Henricus J R van der Horst, Arend Bökenkamp, Johanna M van Hagen, Leonard H van den Berg, Katja P Wolffenbuttel, Joop van den Hoek, Wouter F Feitz, Tom P V M de Jong, Jacques C Giltay, and Cisca Wijmenga
- Subjects
Medicine ,Science - Abstract
Vesico-ureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract and causes 8.5% of end-stage renal disease in children. It is a complex genetic developmental disorder, in which ectopic embryonal ureteric budding is implicated in the pathogenesis. VUR is part of the spectrum of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). We performed an extensive association study for primary VUR using a two-stage, case-control design, investigating 44 candidate genes in the ureteric budding pathway in 409 Dutch VUR patients. The 44 genes were selected from the literature and a set of 567 single nucleotide polymorphisms (SNPs) capturing their genetic variation was genotyped in 207 cases and 554 controls. The 14 SNPs with p
- Published
- 2012
- Full Text
- View/download PDF
6. Fabry disease with atypical phenotype identified by massively parallel sequencing in early-onset kidney failure
- Author
-
Amber de Haan, Chantal F Morel, Mark Eijgelsheim, Margriet F C de Jong, Jan Broekroelofs, Liffert Vogt, Nine V A M Knoers, and Martin H de Borst
- Subjects
Transplantation ,Nephrology - Abstract
Background The cause of chronic kidney disease (CKD) remains unknown in ∼20% of patients with kidney failure. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, with a diagnostic yield of 12%–56%. Here, we report the use of MPS to establish a genetic diagnosis in a 24-year-old index patient who presented with hypertension, nephrotic-range proteinuria and kidney failure of unknown origin. Additionally, we describe a second family with the same mutation presenting with early-onset CKD. Results In Family 1, MPS identified a known pathogenic variant in GLA (p.Ile319Thr), and plasma globotriaosylsphingosine and α-galactosidase A activity were compatible with the diagnosis of Fabry disease (FD). Segregation analysis identified three other family members carrying the same pathogenic variant who had mild or absent kidney phenotypes. One family member was offered enzyme therapy. While FD could not be established with certainty as the cause of kidney failure in the index patient, no alternative explanation was found. In Family 2, the index patient had severe glomerulosclerosis and a kidney biopsy compatible with FD at the age of 30 years, along with cardiac involvement and a history of acroparesthesia since childhood, in keeping with a more classical Fabry phenotype. Conclusion These findings highlight the large phenotypic heterogeneity associated with GLA mutations in FD and underline several important implications of MPS in the work-up of patients with unexplained kidney failure.
- Published
- 2022
7. What’s in a name? That which we call diabetes does not taste sweet!
- Author
-
Detlef Bockenhauer, Nine V. A. M. Knoers, and Daniel G. Bichet
- Subjects
Nephrology ,Pediatrics, Perinatology and Child Health - Published
- 2023
8. mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy
- Author
-
Anukrati Nigam, Deborah P. Jones, Martin Konrad, Claudia Dafinger, Karin Klingel, Stéphane Burtey, Francisco J. Arjona, David M. Sabatini, Carsten Bergmann, Eric Schulze-Bahr, Caro Bos, Pascal Houillier, Rosa Vargas-Poussou, Mehmet Eltan, Holger Thiele, Alina Braun, Tulay Guran, Nine V A M Knoers, Jeroen H. F. de Baaij, Janine Altmüller, Max C. Liebau, Karin Dahan, Nathalie Godefroid, Jun Oh, François Jouret, Holger Rehmann, Felix Kleinerüschkamp, Maria Ibars Serra, Bodo B. Beck, Bernhard Schermer, Karl P. Schlingmann, Kirsten Y. Renkema, Fried J. T. Zwartkruis, Kuang Shen, Jens König, Marie-Christine Parotte, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de pédiatrie générale
- Subjects
MTOR ,Cardiomyopathy ,General Medicine ,mTORC1 ,Biology ,medicine.disease ,Bartter syndrome ,Nephrocalcinosis ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,medicine.anatomical_structure ,Tubulopathy ,Clinical Research ,Nephrology ,TRPM6 ,Cancer research ,medicine ,Hypomagnesemia ,Missense mutation ,Distal convoluted tubule ,genetic renal disease ,hypokalemia ,hypomagnesemia ,kidney stones ,mTOR ,magnesium ,nephrocalcinosis ,rag complex ,salt wasting ,Rag complex - Abstract
Contains fulltext : 244896.pdf (Publisher’s version ) (Closed access) BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis. METHODS: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function. 01 november 2021
- Published
- 2021
9. Behavioral and cognitive functioning in individuals with Cantu syndrome
- Author
-
Lieke M van der Heuvel, Gijs van Haaften, Helen I. Roessler, Kathleen Shields, Mieke M. van Haelst, Dorothy K. Grange, Kristin P. Guilliams, Nine V A M Knoers, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
- Subjects
0301 basic medicine ,Male ,Emotions ,030105 genetics & heredity ,Sulfonylurea Receptors ,Cognition ,Child ,Genetics (clinical) ,Cant-syndrome ,education.field_of_study ,ABNORMALITIES ,HERITABILITY ,Middle Aged ,intelligence ,Phenotype ,Autism spectrum disorder ,Child, Preschool ,Cohort ,Anxiety ,DSM V ,Female ,medicine.symptom ,Clinical psychology ,Adult ,Adolescent ,DEFICIT HYPERACTIVITY DISORDER ,Population ,Hypertrichosis ,autism ,Cardiomegaly ,Osteochondrodysplasias ,Article ,03 medical and health sciences ,Young Adult ,KCNJ8 ,Genetics ,medicine ,Attention deficit hyperactivity disorder ,Humans ,Genetic Predisposition to Disease ,Cognitive skill ,education ,Alleles ,Genetic Association Studies ,Aged ,business.industry ,behavior ,MUTATIONS ,Infant ,medicine.disease ,psychiatric symptoms ,030104 developmental biology ,Mutation ,Autism ,business - Abstract
Cantu syndrome (CS) is caused by pathogenic variants in ABCC9 and KCNJ8 encoding the regulatory and pore-forming subunits of ATP-sensitive potassium (K-ATP) channels. CS is characterized by congenital hypertrichosis, distinctive facial features, peripheral edema, and cardiac and neurodevelopmental abnormalities. Behavioral and cognitive issues have been self-reported by some CS individuals, but results of formal standardized investigations have not been published. To assess the cognitive profile, social functioning, and psychiatric symptoms in a large group of CS subjects systematically in a cross-sectional manner, we invited 35 individuals (1-69 years) with confirmed ABCC9 variants and their relatives to complete various commonly applied standardized age-related questionnaires, including the Kaufman brief intelligence test 2, the social responsiveness scale-2, and the Achenbach system of empirically based assessment. The majority of CS individuals demonstrated average verbal and nonverbal intelligence compared to the general population. Fifteen percent of cases showed social functioning strongly associated with a clinical diagnosis of autism spectrum disorder. Both externalizing and internalizing problems were also present in this cohort. In particular, anxiety, anxiety or attention deficit hyperactivity disorder, and autism spectrum behaviors were predominantly observed in the younger subjects in the cohort (>= 25%), but this percentage decreased markedly in adults.
- Published
- 2021
10. Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice
- Author
-
Carsten Bergmann, Karin Dahan, Beata S. Lipska-Ziętkiewicz, Rosa Vargas-Poussou, Marina Noris, Giuseppe Remuzzi, Franz Schaefer, Laurence Heidet, Nine V A M Knoers, Corinne Antignac, and Sabrina Giglio
- Subjects
Nephrology ,Adult ,medicine.medical_specialty ,Genetic counseling ,Kidney ,genetic testing ,Internal medicine ,Medicine ,Humans ,In patient ,Renal Insufficiency, Chronic ,Intensive care medicine ,AcademicSubjects/MED00340 ,Child ,Special Report ,Genetic testing ,Transplantation ,Modalities ,Massive parallel sequencing ,medicine.diagnostic_test ,business.industry ,massively parallel sequencing ,clinical benefit ,High-Throughput Nucleotide Sequencing ,monogenic diseases ,medicine.disease ,Clinical Practice ,Editor's Choice ,business ,chronic kidney disease ,genetic counselling ,Kidney disease - Abstract
The overall diagnostic yield of massively parallel sequencing–based tests in patients with chronic kidney disease (CKD) is 30% for paediatric cases and 6–30% for adult cases. These figures should encourage nephrologists to frequently use genetic testing as a diagnostic means for their patients. However, in reality, several barriers appear to hinder the implementation of massively parallel sequencing–based diagnostics in routine clinical practice. In this article we aim to support the nephrologist to overcome these barriers. After a detailed discussion of the general items that are important to genetic testing in nephrology, namely genetic testing modalities and their indications, clinical information needed for high-quality interpretation of genetic tests, the clinical benefit of genetic testing and genetic counselling, we describe each of these items more specifically for the different groups of genetic kidney diseases and for CKD of unknown origin.
- Published
- 2021
11. Review of genetic testing in kidney disease patients: Diagnostic yield of single nucleotide variants and copy number variations evaluated across and within kidney phenotype groups
- Author
-
Laura R. Claus, Rozemarijn Snoek, Nine V. A. M. Knoers, and Albertien M. van Eerde
- Subjects
MPS ,DNA Copy Number Variations ,Nucleotides ,CNV ,review ,High-Throughput Nucleotide Sequencing ,Kidney ,Phenotype ,diagnostic yield ,nephrogenetics ,Genetics ,CKD ,Humans ,Genetic Testing ,Renal Insufficiency, Chronic ,Genetics (clinical) - Abstract
Genetic kidney disease comprises a diverse group of disorders. These can roughly be divided in the phenotype groups congenital anomalies of the kidney and urinary tract, ciliopathies, glomerulopathies, stone disorders, tubulointerstitial kidney disease, and tubulopathies. Many etiologies can lead to chronic kidney disease that can progress to end-stage kidney disease. Despite each individual disease being rare, together these genetic disorders account for a large proportion of kidney disease cases. With the introduction of massively parallel sequencing, genetic testing has become more accessible, but a comprehensive analysis of the diagnostic yield is lacking. This review gives an overview of the diagnostic yield of genetic testing across and within the full range of kidney disease phenotypes through a systematic literature search that resulted in 115 included articles. Patient, test, and cohort characteristics that can influence the diagnostic yield are highlighted. Detection of copy number variations and their contribution to the diagnostic yield is described for all phenotype groups. Also, the impact of a genetic diagnosis for a patient and family members, which can be diagnostic, therapeutic, and prognostic, is shown through the included articles. This review will allow clinicians to estimate an a priori probability of finding a genetic cause for the kidney disease in their patients.
- Published
- 2022
12. An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International
- Author
-
Roman-Ulrich Müller, A Lianne Messchendorp, Henrik Birn, Giovambattista Capasso, Emilie Cornec-Le Gall, Olivier Devuyst, Albertien van Eerde, Patrick Guirchoun, Tess Harris, Ewout J Hoorn, Nine V A M Knoers, Uwe Korst, Djalila Mekahli, Yannick Le Meur, Tom Nijenhuis, Albert C M Ong, John A Sayer, Franz Schaefer, Aude Servais, Vladimir Tesar, Roser Torra, Stephen B Walsh, Ron T Gansevoort, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, University of Zurich, Müller, Roman-Ulrich, Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), and Internal Medicine
- Subjects
Male ,2747 Transplantation ,BIOMARKERS ,PROGRESSION ,610 Medicine & health ,Kidney ,VESICLES ,10052 Institute of Physiology ,MANAGEMENT ,EQUATION ,Humans ,ANTAGONIST ,ADPKD ,Transplantation ,vasopressin V2 receptor antagonist ,Science & Technology ,2727 Nephrology ,polycystic kidney disease ,tolvaptan ,Patient Selection ,SALT ,position statement ,Urology & Nephrology ,Polycystic Kidney, Autosomal Dominant ,TRIALS ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Nephrology ,570 Life sciences ,biology ,Female ,Life Sciences & Biomedicine ,Antidiuretic Hormone Receptor Antagonists - Abstract
Approval of the vasopressin V2 receptor antagonist tolvaptan-based on the landmark TEMPO 3:4 trial-marked a transformation in the management of autosomal dominant polycystic kidney disease (ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use. ispartof: NEPHROLOGY DIALYSIS TRANSPLANTATION vol:37 issue:5 pages:825-839 ispartof: location:England status: published
- Published
- 2022
13. The growing power of Kidney Genetics
- Author
-
Nine V A M, Knoers
- Subjects
Genetics ,Humans ,Kidney ,Genetics (clinical) - Published
- 2022
14. The term CAKUT has outlived its usefulness: the case for the defense
- Author
-
Nine V. A. M. Knoers
- Subjects
Vesico-Ureteral Reflux ,MONOZYGOTIC TWINS ,Kidney ,Reduced penetrance ,Shared etiology ,CONGENITAL-ANOMALIES ,DISCORDANT ,AGENESIS ,Nephrology ,Pregnancy ,Chronic kidney disease ,Urogenital Abnormalities ,Pediatrics, Perinatology and Child Health ,Variable expressivity ,Humans ,URINARY-TRACT MALFORMATIONS ,Female ,Urinary Tract ,CAKUT ,Genetic counseling - Abstract
Congenital anomalies of the kidney and urinary tract form a spectrum of congenital structural disorders that are generally known under the term CAKUT. The term CAKUT was introduced 20 years ago and has been used extensively in literature since. Prof. Woolf has made a plea for abandoning this term in his “case for the prosecution.” Here, I advocate for the continued use of CAKUT as an umbrella term for these related congenital kidney and urinary tract abnormalities. I explain why the term CAKUT accurately and usefully defines this group of related structural disorders with prenatal origin and why it makes sense to continue grouping these disorders given accumulating evidence for shared etiology of CAKUT phenotypes and the importance of grouping CAKUT phenotypes in genetic counseling.
- Published
- 2022
15. Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA
- Author
-
Martin Konrad, Rolf Beetz, Marguerite Hureaux, Rosa Vargas-Poussou, Robert Kleta, Günter Klaus, Tom Nijenhuis, Ernie M.H.F. Bongers, Daan M. Panneman, Solenne Pelletier, Richard J. Rodenburg, Martin Kömhoff, André P van Beek, Pascal Houillier, Jean-Marie Coulibaly, Nine V A M Knoers, Marion Vallet, Stéphane Decramer, Melanie Chan, Glenn Anderson, Carsten Bergmann, Detlef Bockenhauer, Mohan Shenoy, Jeroen H. F. de Baaij, Eric J. Steenbergen, Chirag Patel, Albertien M. van Eerde, Karl-Peter Schlingmann, Daan H H M Viering, Andrew Mallett, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
- Subjects
Male ,Kidney ,DISEASE ,ion transport ,Genotype ,Solute Carrier Family 12, Member 3 ,Gitelman-s syndrome ,CHANNEL GENE ,Child ,RNA, Transfer, Ile ,PHOSPHORYLATION ,NCC ,biology ,genetic renal disease ,blood pressure ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,General Medicine ,Middle Aged ,chronic kidney failure ,TUBULE ,Na transport ,Pedigree ,mitochondria ,BARTTER-SYNDROME ,Phenotype ,medicine.anatomical_structure ,Mitochondrial respiratory chain ,MAGNESIUM ,Nephrology ,Child, Preschool ,epithelial sodium transport ,Female ,Gitelman Syndrome ,Adult ,Mitochondrial DNA ,Adolescent ,human genetics ,KCNJ10 ,DNA, Mitochondrial ,Models, Biological ,Polymorphism, Single Nucleotide ,RNA, Transfer, Phe ,Young Adult ,Tubulopathy ,medicine ,Humans ,Distal convoluted tubule ,HYPOMAGNESEMIA ,Aged ,CLCNKB ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,MITOCHONDRIAL-DNA MUTATION ,Base Sequence ,Infant ,Gitelman syndrome ,medicine.disease ,Molecular biology ,SODIUM-CHLORIDE COTRANSPORTER ,HEK293 Cells ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Basic Research ,Mutation ,biology.protein ,Nucleic Acid Conformation ,chronic kidney disease - Abstract
Contains fulltext : 248375.pdf (Publisher’s version ) (Closed access) BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na(+)-Cl(-) cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive (22)Na(+) transport. RESULTS: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. CONCLUSION: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
- Published
- 2022
16. Preimplantation Genetic Testing for Monogenic Kidney Disease
- Author
-
Christine E. M. de Die-Smulders, Klaske D. Lichtenbelt, A. Titia Lely, Jos Dreesen, Franka E. van Reekum, Cindy E. Simcox, Theodora C. van Tilborg, Rozemarijn Snoek, Marijn Stokman, Albertien M. van Eerde, Nine V A M Knoers, Aimee D C Paulussen, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica
- Subjects
ESHRE PGD ,Male ,Pediatrics ,Epidemiology ,030232 urology & nephrology ,Nephritis, Hereditary ,Reproductive technology ,Disease ,Critical Care and Intensive Care Medicine ,0302 clinical medicine ,MARKERS ,Pregnancy ,Risk Factors ,Netherlands ,RISK ,OUTCOMES ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,genetic renal disease ,Polycystic Kidney, Autosomal Dominant ,Autosomal Recessive Polycystic Kidney Disease ,FAMILY ,Nephrology ,Female ,Kidney Diseases ,Live birth ,Adult ,medicine.medical_specialty ,Reproductive Techniques, Assisted ,BIRTH ,Autosomal dominant polycystic kidney disease ,Genetic Counseling ,DIAGNOSIS ,Young Adult ,03 medical and health sciences ,Predictive Value of Tests ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Preimplantation Diagnosis ,ADPKD ,Polycystic Kidney, Autosomal Recessive ,Retrospective Studies ,Genetic testing ,Transplantation ,MEDICINE ,business.industry ,Editorials ,Retrospective cohort study ,Original Articles ,medicine.disease ,Mutation ,business ,Alport syndrome ,Kidney disease - Abstract
Background and objectives: A genetic cause can be identified for an increasing number of pediatric and adult-onset kidney diseases. Preimplantation genetic testing (formerly known as preimplantation genetic diagnostics) is a reproductive technology that helps prospective parents to prevent passing on (a) disease-causing mutation(s) to their offspring. Here, we provide a clinical overview of 25 years of preimplantation genetic testing for monogenic kidney disease in The Netherlands.Design, setting, participants, & measurements: This is a retrospective cohort study of couples counseled on preimplantation genetic testing for monogenic kidney disease in the national preimplantation genetic testing expert center (Maastricht University Medical Center+) from January 1995 to June 2019. Statistical analysis was performed through chi-squared tests.Results: In total, 98 couples were counseled regarding preimplantation genetic testing, of whom 53% opted for preimplantation genetic testing. The most frequent indications for referral were autosomal dominant polycystic kidney disease (38%), Alport syndrome (26%), and autosomal recessive polycystic kidney disease (9%). Of couples with at least one preimplantation genetic testing cycle with oocyte retrieval, 65% experienced one or more live births of an unaffected child. Of couples counseled, 38% declined preimplantation genetic testing for various personal and technical reasons.Conclusions: Referrals, including for adult-onset disease, have increased steadily over the past decade. Though some couples decline preimplantation genetic testing, in the couples who proceed with at least one preimplantation genetic testing cycle, almost two thirds experienced at least one live birth rate.
- Published
- 2020
17. Inherited Disorders of Water Handling
- Author
-
Nine V. A. M. Knoers, Elena Levtchenko, and Daniel G. Bichet
- Subjects
X-linked ,Arginine vasopressin type 2 receptor ,Anticipatory thirst ,Congenital nephrogenic diabetes insipidus ,Polyuria ,Autosomal ,Aqp2 water channel ,Arginine vasopressin ,Acquired nephrogenic diabetes insipidus ,Nephrogenic syndrome of inappropriate antidiuresis - Abstract
Under normal circumstances, about 90% of the 180 L/day glomerular filtrate is constitutively reabsorbed in the proximal tubule and descending limb of Henle’s loop. According to the needs, the remaining 10% of the fluid is reabsorbed in the collecting duct by a tightly regulated process under control of arginine vasopressin (AVP). After binding of AVP to arginine vasopressin type 2 receptors (AVPR2) in the basolateral membrane of collecting duct cells, aquaporin-2 (AQP2) water channels are inserted into the luminal membrane of these cells, allowing water reabsorption and urine concentration. Disorders of water handling are characterized by disturbances of this AVP-regulated system. In congenital nephrogenic diabetes insipidus (NDI), the kidney cannot concentrate urine in response to AVP, as a result of loss-of-function mutations in genes encoding AVPR2 and AQP2, resulting in polyuria and polydipsia. In recent years, extensive research has led to increased understanding of the cellular defects in NDI, with important implications for future development of targeted treatment of the disorder, with hope for better outcomes in comparison to the conventional symptomatic therapy. The very rare nephrogenic syndrome of inappropriate antidiuresis (NSIAD), caused by gain-of-function mutations in the gene encoding AVPR2, is the mirror image of NDI. In this disorder, urinary dilution is impaired, independent of the presence or absence of AVP. In this chapter, the focus will be on the physiology of water handling in the collecting duct and on its disturbances in congenital NDI. The clinical details, differential diagnosis, genetics, and conventional and possible future therapies of NDI will be discussed in detail.
- Published
- 2022
18. Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa
- Author
-
Aileen Sandilands, Henny H. Lemmink, Anna M.G. Pasmooij, Robert J Sietsma, Robyn P. Hickerson, Peter C. Van Den Akker, K. Joeri van der Velde, Jeroen Bremer, Morris A. Swertz, Nine V A M Knoers, Marieke C. Bolling, and Franciscus C Vermeer
- Subjects
EXPRESSION ,antisense oligonucleotide ,VII COLLAGEN ,QH301-705.5 ,Review ,FORMS ,PHENOTYPE ,Bioinformatics ,ANTISENSE OLIGONUCLEOTIDES ,Catalysis ,Inorganic Chemistry ,DELIVERY ,Exon ,medicine ,Humans ,epidermolysis bullosa ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Gene ,Spectroscopy ,Skin ,integumentary system ,MUTATIONS ,business.industry ,DELETION ,Organic Chemistry ,RNA ,General Medicine ,Exons ,Fibroblasts ,Oligonucleotides, Antisense ,medicine.disease ,Phenotype ,Symptomatic relief ,Exon skipping ,Computer Science Applications ,Chemistry ,Open reading frame ,SEVERITY ,Mutation ,Epidermolysis bullosa ,business ,exon skipping - Abstract
Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes.
- Published
- 2021
19. Strategies in Rapid Genetic Diagnostics of Critically Ill Children
- Author
-
Wilhelmina S. Kerstjens-Frederikse, Martine T. Meems-Veldhuis, Nine V. A. M. Knoers, Dennis K. Bos, Miriam E. Imafidon, Birgit Sikkema-Raddatz, Cleo C. van Diemen, Gea Beunders, Morris A. Swertz, Kristin M. Abbott, K. Joeri van der Velde, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
- Subjects
medicine.medical_specialty ,Pediatrics ,Neonatal intensive care unit ,Referral ,MEDICAL GENETICS ,Physical examination ,AMERICAN-COLLEGE ,RJ1-570 ,03 medical and health sciences ,genetic disease ,Intensive care ,medicine ,Medical diagnosis ,genetic diagnostics ,CLINICAL EXOME ,Original Research ,030304 developmental biology ,Genetic testing ,next generation sequencing ,0303 health sciences ,medicine.diagnostic_test ,business.industry ,030305 genetics & heredity ,copy number variation ,University hospital ,neonatal intensive care (unit) ,Pediatrics, Perinatology and Child Health ,Medical genetics ,business - Abstract
Background: Genetic disorders are a substantial cause of infant morbidity and mortality and are frequently suspected in neonatal intensive care units. Non-specific clinical presentation or limitations to physical examination can result in a plethora of genetic testing techniques, without clear strategies on test ordering. Here, we review our 2-years experiences of rapid genetic testing of NICU patients in order to provide such recommendations.Methods: We retrospectively included all patients admitted to the NICU who received clinical genetic consultation and genetic testing in our University hospital. We documented reasons for referral for genetic consultation, presenting phenotypes, differential diagnoses, genetic testing requested and their outcomes, as well as the consequences of each (rapid) genetic diagnostic approach. We calculated diagnostic yield and turnaround times (TATs).Results: Of 171 included infants that received genetic consultation 140 underwent genetic testing. As a result of testing as first tier, 13/14 patients received a genetic diagnosis from QF-PCR; 14/115 from SNP-array; 12/89 from NGS testing, of whom 4/46 were diagnosed with a small gene panel and 8/43 with a large OMIM-morbid based gene panel. Subsequent secondary or tertiary analysis and/or additional testing resulted in five more diagnoses. TATs ranged from 1 day (QF-PCR) to a median of 14 for NGS and SNP-array testing, with increasing TAT in particular when many consecutive tests were performed. Incidental findings were detected in 5/140 tested patients (3.6%).Conclusion: We recommend implementing a broad NGS gene panel in combination with CNV calling as the first tier of genetic testing for NICU patients given the often unspecific phenotypes of ill infants and the high yield of this large panel.
- Published
- 2021
20. FC 012PRIMARY KIDNEY DISEASE IMPACTS OUTCOME IN CKD PREGNANCIES: COMPLICATIONS IN COL4A3-5 RELATED DISEASE (ALPORT SYNDROME) VS OTHER CKD PREGNANCIES
- Author
-
Titia Lely, Margriet Gosselink, Margriet F C de Jong, Renee Vollenberg, Liffert Vogt, Agne Cerkauskaite, Rozemarijn Snoek, Albertien M. van Eerde, and Nine V A M Knoers
- Subjects
Transplantation ,Pediatrics ,medicine.medical_specialty ,Fetus ,business.industry ,Hypertension in Pregnancy ,Disease ,medicine.disease ,Causality ,Nephrology ,medicine ,Alport syndrome ,business ,Kidney disease - Abstract
Background and Aims Chronic kidney disease (CKD) affects approximately 3% of pregnant women. CKD increases the risk of pregnancy complications such as prematurity, low birthweight and pre-eclampsia. Also, kidney function can deteriorate more quickly due to pregnancy. There is limited knowledge on pregnancy outcomes in specific kidney diseases. The aim of the ALPART network is to study pregnancy outcomes differentiated by CKD aetiology. We have started with COLA3-5 related disease (Alport syndrome), which is one of the most prevalent monogenic kidney diseases. Comparing outcomes in COLA3-5 related disease to pregnancies with other CKD aetiologies allows us to investigate whether this specific diagnosis impacts outcome in CKD pregnancies. Method The ALPART network is an international 15-center network, which aims to include ∼200 COLA3-5 related disease pregnancies. In this intermediary analysis, we present data on 109 pregnancies from 68 women with COLA3-5 related disease. We compared outcomes to a cohort of 457 CKD stage 1-2 patients (a similar CKD stage as our cohort) of diverse aetiology from a 2015 Italian study and 159,924 women from the general Dutch population. Results The main pregnancy and kidney outcomes are presented in Figure 1. Foetal outcomes were better in COLA3-5 pregnancies than in pregnancies of women with CKD stage 1-2 of diverse aetiology. We saw less prematurity (17% vs 36% respectively) and a higher mean birthweight of 3216 ± 663 gram compared to 2768 ± 680 in the Italian cohort. Maternal kidney outcomes should be interpreted with caution (>30% missing data): proteinuria (73%) and hypertension (30%) were more frequent in COLA3-5 pregnancies than the Italian cohort. In the ALPART cohort, 10% developed severe hypertension. Median eGFR was not impacted by pregnancy and decline of eGFR before and after pregnancy were not significantly different between groups. Conclusion Fetal outcomes in pregnancies with COLA3-5 related disease seem to be more favorable than in a cohort with mixed cause of CKD. In this intermediary analysis, proteinuria levels and frequency of new-onset hypertension in pregnancy are higher. There is no significant eGFR loss during pregnancy or increased eGFR deterioration in the long-term. The differences between COLA3-5 and general CKD pregnancies underscore the importance of investigating pregnancy outcomes in specific kidney disease phenotypes to ensure adequate (pre-) pregnancy counselling and care.
- Published
- 2021
21. FC 011KIDNEYNETWORK: USING KIDNEY DERIVED GENE EXPRESSION DATA TO PREDICT AND PRIORITIZE NOVEL GENES INVOLVED IN KIDNEY DISEASE
- Author
-
Henry Wiersma, Lude Franke, Floor Schukking, Jan Halbritter, Floranne Boulogne, Shuang Li, Harm-Jan Westra, Nine V A M Knoers, Niek de Klein, Albertien M. van Eerde, Franka E. van Reekum, Roy Oelen, Bert van der Zwaag, Laura R. Claus, and Patrick Deelen
- Subjects
Transplantation ,Kidney ,business.industry ,Computational biology ,medicine.disease ,Novel gene ,medicine.anatomical_structure ,Text mining ,Nephrology ,Fibrosis ,Gene expression ,medicine ,business ,Candidate Disease Gene ,Gene ,Kidney disease - Abstract
Background and Aims Genetic testing in patients with suspected hereditary kidney disease does not always reveal the genetic cause for the patient's disorder. Potentially pathogenic variants can reside in genes that are not known to be involved in kidney disease, which makes it difficult to prioritize and interpret the relevance of these variants. As such, there is a clear need for methods that predict the phenotypic consequences of gene expression in a way that is as unbiased as possible. To help identify candidate genes we have developed KidneyNetwork, in which tissue-specific expression is utilized to predict kidney-specific gene functions. Method We combined gene co-expression in 878 publicly available kidney RNA-sequencing samples with the co-expression of a multi-tissue RNA-sequencing dataset of 31,499 samples to build KidneyNetwork. The expression patterns were used to predict which genes have a kidney-related function, and which (disease) phenotypes might be caused when these genes are mutated. By integrating the information from the HPO database, in which known phenotypic consequences of disease genes are annotated, with the gene co-expression network we obtained prediction scores for each gene per HPO term. As proof of principle, we applied KidneyNetwork to prioritize variants in exome-sequencing data from 13 kidney disease patients without a genetic diagnosis. Results We assessed the prediction performance of KidneyNetwork by comparing it to GeneNetwork, a multi-tissue co-expression network we previously developed. In KidneyNetwork, we observe a significantly improved prediction accuracy of kidney-related HPO-terms, as well as an increase in the total number of significantly predicted kidney-related HPO-terms (figure 1). To examine its clinical utility, we applied KidneyNetwork to 13 patients with a suspected hereditary kidney disease without a genetic diagnosis. Based on the HPO terms “Renal cyst” and “Hepatic cysts”, combined with a list of potentially damaging variants in one of the undiagnosed patients with mild ADPKD/PCLD, we identified ALG6 as a new candidate gene. ALG6 bears a high resemblance to other genes implicated in this phenotype in recent years. Through the 100,000 Genomes Project and collaborators we identified three additional patients with kidney and/or liver cysts carrying a suspected deleterious variant in ALG6. Conclusion We present KidneyNetwork, a kidney specific co-expression network that accurately predicts what genes have kidney-specific functions and may result in kidney disease. Gene-phenotype associations of genes unknown for kidney-related phenotypes can be predicted by KidneyNetwork. We show the added value of KidneyNetwork by applying it to exome sequencing data of kidney disease patients without a molecular diagnosis and consequently we propose ALG6 as a promising candidate gene. KidneyNetwork can be applied to clinically unsolved kidney disease cases, but it can also be used by researchers to gain insight into individual genes to better understand kidney physiology and pathophysiology. Acknowledgments This research was made possible through access to the data and findings generated by the 100,000 Genomes Project; http://www.genomicsengland.co.uk.
- Published
- 2021
22. A validated PROM in genetic counselling: the psychometric properties of the Dutch version of the Genetic Counselling Outcome Scale
- Author
-
Mirjam Plantinga, Irene M. van Langen, Adelita V. Ranchor, Wim P. Krijnen, Nine V A M Knoers, Mary E. Velthuizen, Erwin Birnie, Anneke Lucassen, Jan S Voorwinden, Margreet G. E. M. Ausems, Reproductive Origins of Adult Health and Disease (ROAHD), and Health Psychology Research (HPR)
- Subjects
Male ,medicine.medical_specialty ,Psychometrics ,Genetic counseling ,Genetic Counseling ,Prom ,Article ,03 medical and health sciences ,Surveys and Questionnaires ,Intellectual disability ,Journal Article ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Patient Reported Outcome Measures ,Genetics (clinical) ,Netherlands ,0303 health sciences ,030305 genetics & heredity ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Convergent validity ,Scale (social sciences) ,Medical genetics ,Female ,Patient-reported outcome ,Factor Analysis, Statistical ,Psychology ,Clinical psychology - Abstract
Patient empowerment has been identified as a key outcome goal in genetic counselling, and a patient reported outcome measure (PROM) has been developed to measure empowerment in genetic services: the Genetic Counselling Outcome Scale (GCOS). Here we validate the GCOS for a large and diverse Dutch study sample of 2194 patients referred to two clinical genetic centres for counselling about a wide range of conditions (heart disease, neurological disorders, cancer, congenital syndromes, intellectual disability and prenatal pathology). Our results suggest that the GCOS consists of a hierarchical 6-factor structure, with a main scale for empowerment and six subscales: uncertainty about heredity, hope, negative emotions, knowledge about the condition, knowledge about genetic services and uncertainty about the treatment. Six of the original 24 GCOS items were removed due to low factor loadings and small inter-item correlations. Internal consistency and test-retest reliability of the main scale and most subscales were satisfactory. Convergent validity was confirmed by moderate positive and moderate/strong negative associations between the GCOS main scale and other validated outcome measures. Responsiveness was comparable to that of other validated outcome measures. We saw significant improvement in the GCOS main scale and all the subscales after the first genetic counselling session. This study contributes to the international validation process of the GCOS, with the ultimate goal of using this instrument as a PROM, with empowerment as an outcome measure, to evaluate and improve the quality of genetic counselling in various clinical genetics settings.
- Published
- 2019
23. 6th Update on Fabry Disease: Biomarkers, Progression and Treatment Opportunities
- Author
-
Armin Kurtz, Richard Coward, Angela Yee-Moon Wang, Chih-Wei Yang, Carsten A. Wagner, Volker Vallon, Claudio Ronco, Duncan T. Wilcox, Julia Hoefele, Alain Doucet, Csaba P. Kovesdy, Fabiola Terzi, Giuseppe Remuzzi, Kamyar Kalantar-Zadeh, Manuela Passera, Martin H. de Borst, Andrew Davenport, Florian Lang, Alain Meyrier, Druckerei Stückle, Masaomi Nangaku, Ken Farrington, Nine V A M Knoers, John Cijiang He, Lars Christian Rump, Ariela Benigni, Krishna M. Boini, Philip Poronnik, Visith Thongboonkerd, Berthold Hocher, Jeremy Hughes, Peter Stenvinkel, David G. Warnock, T. Gilbert, Kenji Osafune, Lorenzo Gallon, and Fernando Martin-Belmonte
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,business ,medicine.disease ,Fabry disease - Published
- 2019
24. Drug Repurposing for Rare Diseases
- Author
-
Nine V A M Knoers, Gijs van Haaften, Mieke M. van Haelst, and Helen I. Roessler
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Orphan Drug Production ,Population ,Toxicology ,Unmet needs ,Orphan drug ,03 medical and health sciences ,0302 clinical medicine ,Rare Diseases ,Medicine ,Humans ,Intensive care medicine ,education ,Repurposing ,Pharmacology ,education.field_of_study ,Drug discovery ,business.industry ,Drug Repositioning ,Treatment options ,Drug repositioning ,030104 developmental biology ,Drug development ,business ,030217 neurology & neurosurgery - Abstract
Currently, there are about 7000 identified rare diseases, together affecting 10% of the population. However, fewer than 6% of all rare diseases have an approved treatment option, highlighting their tremendous unmet needs in drug development. The process of repurposing drugs for new indications, compared with the development of novel orphan drugs, is a time-saving and cost-efficient method resulting in higher success rates, which can therefore drastically reduce the risk of drug development for rare diseases. Although drug repurposing is not novel, new strategies have been developed in recent years to do it in a systematic and rational way. Here, we review applied methodologies, recent accomplished progress, and the challenges associated in drug repurposing for rare diseases.
- Published
- 2021
25. KidneyNetwork: Using kidney-derived gene expression data to predict and prioritize novel genes involved in kidney disease
- Author
-
Henry Wiersma, Dana Sierks, Niek de Klein, Patrick Deelen, Floranne Boulogne, Ria Schönauer, Bert van der Zwaag, Franka E. van Reekum, Jan Halbritter, Floor Schukking, Roy Oelen, Shuang Li, Harm-Jan Westra, Lude Franke, Albertien M. van Eerde, Laura R. Claus, and Nine V A M Knoers
- Subjects
Cystic kidney ,Candidate gene ,medicine.diagnostic_test ,Genetic variation ,medicine ,Computational biology ,Disease ,Biology ,medicine.disease ,Gene ,Exome sequencing ,Genetic testing ,Kidney disease - Abstract
BackgroundGenetic testing in patients with suspected hereditary kidney disease may not reveal the genetic cause for the disorder as potentially pathogenic variants can reside in genes that are not yet known to be involved in kidney disease. To help identify these genes, we have developed KidneyNetwork, that utilizes tissue-specific expression to predict kidney-specific gene functions.MethodsKidneyNetwork is a co-expression network built upon a combination of 878 kidney RNA-sequencing samples and a multi-tissue dataset of 31,499 samples. It uses expression patterns to predict which genes have a kidney-related function and which (disease) phenotypes might result from variants in these genes. We applied KidneyNetwork to prioritize rare variants in exome sequencing data from 13 kidney disease patients without a genetic diagnosis.ResultsKidneyNetwork can accurately predict kidney-specific gene functions and (kidney disease) phenotypes for disease-associated genes. Applying it to exome sequencing data of kidney disease patients allowed us to identify a promising candidate gene for kidney and liver cysts: ALG6.ConclusionWe present KidneyNetwork, a kidney-specific co-expression network that accurately predicts which genes have kidney-specific functions and can result in kidney disease. We show the added value of KidneyNetwork by applying it to kidney disease patients without a molecular diagnosis and consequently, we propose ALG6 as candidate gene in one of these patients. KidneyNetwork can be applied to clinically unsolved kidney disease cases, but it can also be used by researchers to gain insight into individual genes in order to better understand kidney physiology and pathophysiology.Significance statementGenetic testing in patients with suspected hereditary kidney disease may not reveal the genetic cause for the patient’s disorder. Potentially pathogenic variants can reside in genes not yet known to be involved in kidney disease, making it difficult to interpret the relevance of these variants. This reveals a clear need for methods to predict the phenotypic consequences of genetic variation in an unbiased manner. Here we describe KidneyNetwork, a tool that utilizes tissue-specific expression to predict kidney-specific gene functions. Applying KidneyNetwork to a group of undiagnosed cases identified ALG6 as a candidate gene in cystic kidney and liver disease. In summary, KidneyNetwork can aid the interpretation of genetic variants and can therefore be of value in translational nephrogenetics and help improve the diagnostic yield in kidney disease patients.
- Published
- 2021
26. Clinical versus research genomics in kidney disease
- Author
-
Andrew Mallett, John A. Sayer, Nine V A M Knoers, and Zornitza Stark
- Subjects
0301 basic medicine ,Nephrology ,medicine.medical_specialty ,Clinical genomics ,GENETICS ,business.industry ,030232 urology & nephrology ,MEDLINE ,Genomics ,medicine.disease ,03 medical and health sciences ,Patient benefit ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,medicine ,Personalized medicine ,Medical diagnosis ,business ,Intensive care medicine ,Kidney disease - Abstract
Key differences exist between clinical and research genomics. As genomic testing is adopted in nephrology clinical care, we propose focusing on clinical genomics approaches to obtain genetic diagnoses in order to ensure optimal use of resources and maximum patient benefit.
- Published
- 2021
27. Diagnostic yield of massively parallel sequencing in patients with chronic kidney disease of unknown etiology: rationale and design of a national prospective cohort study
- Author
-
Amber de Haan, Mark Eijgelsheim, Liffert Vogt, Bert van der Zwaag, Albertien M van Eerde, Nine V A M Knoers, Martin H de Borst, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Nephrology, ACS - Microcirculation, and APH - Health Behaviors & Chronic Diseases
- Subjects
GENETICS ,High-Throughput Nucleotide Sequencing ,Chronic/diagnosis ,General Medicine ,Middle Aged ,Chronic renal failure ,Disease Progression ,End stage renal failure ,Humans ,Renal Insufficiency ,Prospective Studies ,Renal Insufficiency, Chronic ,NEPHROLOGY ,Renal Insufficiency, Chronic/diagnosis ,Glomerular Filtration Rate ,Retrospective Studies - Abstract
IntroductionChronic kidney disease (CKD) can be caused by a variety of systemic or primary renal diseases. The cause of CKD remains unexplained in approximately 20% of patients. Retrospective studies indicate that massively parallel sequencing (MPS)-based gene panel testing may lead to a genetic diagnosis in 12%–56% of patients with unexplained CKD, depending on patient profile. The diagnostic yield of MPS-based testing in a routine healthcare setting is unclear. Therefore, the primary aim of the VARIETY (Validation of algoRithms and IdEnTification of genes in Young patients with unexplained CKD) study is to prospectively address the diagnostic yield of MPS-based gene panel testing in patients with unexplained CKD and an estimated glomerular filtration rate (eGFR) 2 before the age of 50 years in clinical practice.Methods and analysisThe VARIETY study is an ongoing, prospective, nationwide observational cohort study to investigate the diagnostic yield of MPS-based testing in patients with unexplained CKD in a routine healthcare setting in the Netherlands. Patients are recruited from outpatient clinics in hospitals across the Netherlands. At least 282 patients will be included to meet the primary aim. Secondary analyses include subgroup analyses according to age and eGFR at first presentation, family history, and the presence of extrarenal symptoms.Ethics and disseminationEthical approval for the study has been obtained from the institutional review board of the University Medical Center Groningen. Study findings should inform physicians and policymakers towards optimal implementation of MPS-based diagnostic testing in patients with unexplained CKD.
- Published
- 2022
28. Genetics-first approach improves diagnostics of ESKD patients50 years old
- Author
-
Maarten B. Rookmaaker, Albertien M. van Eerde, Roel Goldschmeding, Tri Q. Nguyen, Bert van der Zwaag, Richard H. van Jaarsveld, Robert F Ernst, Edith D.J. Peters, Eric Spierings, Arjan D. van Zuilen, Rozemarijn Snoek, Marc R. Lilien, Nine V A M Knoers, and Martin G Elferink
- Subjects
0301 basic medicine ,030232 urology & nephrology ,Disease ,Genetic analysis ,Monogenic disease ,Kidney transplant ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Biopsy ,Medicine ,Humans ,Genetic Testing ,Renal Insufficiency, Chronic ,Exome sequencing ,Genetic testing ,Retrospective Studies ,Genetics ,Transplantation ,medicine.diagnostic_test ,business.industry ,Middle Aged ,030104 developmental biology ,Nephrology ,Cohort ,Kidney Failure, Chronic ,business - Abstract
Background Often only chronic kidney disease (CKD) patients with high likelihood of genetic disease are offered genetic testing. Early genetic testing could obviate the need for kidney biopsies, allowing for adequate prognostication and treatment. To test the viability of a ‘genetics-first’ approach for CKD, we performed genetic testing in a group of kidney transplant recipients aged Methods From a cohort of 273 transplant patients, we selected 110 that were in care in the University Medical Center Utrecht, had DNA available and were without clear-cut non-genetic disease. Forty patients had been diagnosed with a genetic disease prior to enrollment; in 70 patients, we performed a whole-exome sequencing-based 379 gene panel analysis. Results Genetic analysis yielded a diagnosis in 51%. Extrapolated to the 273 patient cohort, who did not all fit the inclusion criteria, the diagnostic yield was still 21%. Retrospectively, in 43% of biopsied patients, the kidney biopsy would not have had added diagnostic value if genetic testing had been performed as a first-tier diagnostic. Conclusions The burden of monogenic disease in transplant patients with end-stage kidney disease (ESKD) of any cause prior to the age of 50 years is between 21% and 51%. Early genetic testing can provide a non-invasive diagnostic, impacting prognostication and treatment, and obviating the need for an invasive biopsy. We conclude that in patients who expect to develop ESKD prior to the age of 50 years, genetic testing should be considered as first mode of diagnostics.
- Published
- 2020
29. Cognitive and affective outcomes of genetic counselling in the Netherlands at group and individual level: a personalized approach seems necessary
- Author
-
Mirjam Plantinga, Jan S Voorwinden, Irene M. van Langen, Margreet G. E. M. Ausems, Nine V A M Knoers, Adelita V. Ranchor, Mary E. Velthuizen, Anneke Lucassen, Erwin Birnie, Health Psychology Research (HPR), and Reproductive Origins of Adult Health and Disease (ROAHD)
- Subjects
0303 health sciences ,Operationalization ,Referral ,Genetic counseling ,media_common.quotation_subject ,030305 genetics & heredity ,MEDLINE ,Cognition ,GOALS ,CANCER ,BREAST ,Test (assessment) ,PSYCHOSOCIAL PROBLEMS ,03 medical and health sciences ,Genetics ,medicine ,Anxiety ,medicine.symptom ,Psychology ,Empowerment ,PSYCHOLOGICAL IMPACT ,Genetics (clinical) ,Clinical psychology ,media_common - Abstract
We performed a large outcome study at group and individual level in which the goals of genetic counselling were operationalized into cognitive and affective outcomes: empowerment, perceived personal control and anxiety. We then examined which socio-demographic and clinical variables were associated with changes in these outcomes. Data came from 1479 counselees who completed questionnaires (GCOS-18, PPC and STAI) at three time points: before the start of genetic counselling, after the first consultation and after the results of genetic counselling were disclosed. Results showed that at group level empowerment, perceived personal control and anxiety improved significantly after the whole genetic counselling process. Effect-sizes were medium for empowerment and small for the other outcomes. At individual level, 48% of counselees improved in empowerment, 21% in perceived personal control and 17% in anxiety. Around 10% of counselees worsened on all outcomes. Only 'reason for referral' and 'genetic test result' were significantly associated with changes in outcomes. This study demonstrated improvements among counselees in cognitive and affective outcomes after genetic counselling at group level. However, our results also suggest that there are opportunities for improvement at individual level, as many counselees remained stable and some even worsened on all outcomes. Routine outcome monitoring could help to explore the needs of counselees and could help to identify counselees who worsen.
- Published
- 2020
30. P0050PRE-IMPLANTATION GENETIC TESTING FOR MONOGENIC KIDNEY DISEASE: TWENTY-FIVE YEAR EXPERIENCE IN THE NETHERLANDS
- Author
-
Klaske D. Lichtenbelt, Franka E. van Reekum, Nine V A M Knoers, Albertien M. van Eerde, Christine E. M. de Die-Smulders, Marijn Stokman, Theodora C. van Tilborg, Cindy E. Simcox, Aimee D C Paulussen, Rozemarijn Snoek, and Jos C M F Dreessen
- Subjects
Transplantation ,Pediatrics ,medicine.medical_specialty ,medicine.diagnostic_test ,Nephrology ,business.industry ,medicine ,medicine.disease ,business ,Genetic testing ,Kidney disease - Abstract
Background and Aims Due to the fast-paced developments in human genetics, a genetic cause can now be identified for an increasing number of pediatric and adult-onset kidney diseases. A monogenic kidney disease (MKD) can impact prognostication and therapy decisions. It also provides patients with options regarding family planning such as preimplantation genetic testing (PGT), a reproductive technology that helps prospective parents prevent passing on a disease-causing mutation to their offspring. There are limited reports on PGT for MKD and most are focused on severe pediatric-onset diseases. The Dutch system of insurance reimbursement and nationwide regulation is unique, and it has allowed the Netherlands to be one of a handful of countries where couples have the option to choose PGT for MKD, including adult-onset forms of kidney disease. Here we provide the 25-year Dutch experience with PGT for MKD. Method We performed a retrospective cohort study of all couples counselled on PGT for MKD in the Maastricht University Medical Center+, the expert centre where all Dutch single cell genetic testing on embryos is performed, from January 1995 until June 2019. Results 99 couples were counseled for PGT, of which currently 15% is waiting for the genetic test to be validated. In the early years of PGT for MKD, referrals were incidental and only for couples at risk for offspring with paediatric-onset disease. From 2009 onwards, the number of referrals has steadily increased as has the number of couples referred for adult-onset MKD. Overall, the most frequent indications for referral for PGT were ADPKD (37%), X-linked Alport syndrome (25%) and ARPKD (9%). After counselling, 36% of n=99 couples started PGT treatment. In total n=80 cycles with oocyte retrieval were performed (median 2 cycles [range 1-4]). These cycles led to a median of n=10 embryos (range 2-31) suitable for biopsy and a median of n=3 embryos (range 1-14) being genetically unaffected. Seventy-five percent (n=) of couples achieved at least one live birth. Of n=99, 48% did not proceed with PGT, for various personal and technical reasons. Major reasons for opting out of PGT were that prospective parents did not want to wait for the lengthy PGT procedure (9%) or had a wish for natural conception with prenatal genetic testing (11%). Live birth rate was 40% (n=19) in the non-PGT group, with notably a similar duration to a live birth as the PGT group (2 years, range 0-5 years). Conclusion We provide the largest overview to date of the indications, uptake and results of PGT for MKD. Referrals for PGT, including adult-onset disease, have increased steadily over the past decade. PGT has favorable outcomes, with 75% of couples having at least one live birth, though this is likely due to our small sample size. Genetic and reproductive counseling, including information on PGT, should be provided to all patients and prospective parents from families with MKD to enable informed decision making.
- Published
- 2020
31. Three-dimensional facial morphology in Cantú syndrome
- Author
-
Kathleen Shields, Peter Hammond, Nine V A M Knoers, Gijs van Haaften, Mieke M. van Haelst, Dorothy K. Grange, Helen I. Roessler, Amsterdam Reproduction & Development (AR&D), and Human genetics
- Subjects
Cantú syndrome ,Adult ,Male ,Adolescent ,Genetic counseling ,Hypertrichosis ,Mutation, Missense ,Cardiomegaly ,dense surface model (DSM) ,Osteochondrodysplasias ,Sulfonylurea Receptors ,PHENOTYPE ,Face shape ,ABCC9 ,Young Adult ,Imaging, Three-Dimensional ,KATP Channels ,3D imaging ,KCNJ8 ,Genetics ,Medicine ,Humans ,Genetic Predisposition to Disease ,principal component analysis (PCA) ,Child ,Genetics (clinical) ,Principal Component Analysis ,business.industry ,Coarse facial features ,MUTATIONS ,Long philtrum ,Facial morphology ,Genetic Diseases, X-Linked ,dysmorphology ,Anatomy ,Original Articles ,medicine.disease ,Osteochondrodysplasia ,Child, Preschool ,Face ,Cantu syndrome ,facial phenotyping ,Original Article ,Female ,business ,FACE SHAPE - Abstract
Cantú syndrome (CS) was first described in 1982, and is caused by pathogenic variants in ABCC9 and KCNJ8 encoding regulatory and pore forming subunits of ATP-sensitive potassium (KATP) channels, respectively. It is characterized by congenital hypertrichosis, osteochondrodysplasia, extensive cardiovascular abnormalities and distinctive facial anomalies including a broad nasal bridge, long philtrum, epicanthal folds, and prominent lips. Many genetic syndromes, such as CS, involve facial anomalies that serve as a significant clue in the initial identification of the respective disorder before clinical or molecular diagnosis are undertaken. However, an overwhelming number of CS patients receive misdiagnoses based on an evaluation of coarse facial features. By analyzing three-dimensional images of CS faces, we quantified facial dysmorphology in a cohort of both male and female CS patients with confirmed ABCC9 variants. Morphometric analysis of different regions of the face revealed gender-specific significant differences in face shape. Moreover, we show that 3D facial photographs can distinguish between CS and other genetic disorders with specific facial dysmorphologies that have been mistaken for CS-associated anomalies in the past, hence assisting in an earlier clinical and molecular diagnosis. This optimizes genetic counseling and reduces stress for patients and parents by avoiding unnecessary misdiagnosis.
- Published
- 2020
32. Disorders of tubular electrolyte handling
- Author
-
Elena Levtchenko and Nine V A M Knoers
- Subjects
Chemical engineering ,Chemistry ,Electrolyte - Abstract
Glycosuria—glucose reabsorption in the proximal tubule is carried out by two different pairs of apical Na+-dependent (SGLT1 and -2) and basolateral Na+-independent (GLUT1 and -2) glucose transporters. Abnormalities in renal glucose transport can be seen in association with other defects of proximal tubular transport. Familial renal glycosuria is a rare autosomal recessive condition caused by mutations in the SGLT2-encoding gene, SLC5A2. Phosphate-handling disorders—the plasma concentration of inorganic phosphate depends on the balance between intestinal absorption, renal excretion, and the internal contribution from bone. Changes of serum phosphate levels can be caused by numerous inherited and acquired conditions. Disorders associated with increased urinary phosphate excretion and low serum phosphate levels produce symptoms that mainly affect the bones: rickets in children and osteomalacia in adults. Magnesium-handling disorders—normal plasma magnesium concentration is achieved by variation of urinary magnesium excretion in response to altered uptake by the intestine. The main site of magnesium absorption is the small bowel, via paracellular simple diffusion at high intraluminal concentrations, and via active transcellular uptake through the magnesium channel TRPM6 at low concentrations. Regulation and fine-tuning of serum magnesium concentration occurs primarily in the kidney. Genetic disorders of magnesium handling include Gitelman’s syndrome. Aminoaciduria and renal Fanconi’s syndrome—most amino acids (except for tryptophan, which is protein bound) are freely filtered by the glomerulus, after which 95 to 99.9% are reabsorbed in the proximal tubules by apical Na+-dependent cotransporters and Na+-independent cotransporters. Aminoaciduria is defined as urinary excretion of more than 5% of the filtered load of an amino acid. Renal Fanconi’s syndrome is characterized by a generalized defect of both Na+-coupled and receptor-mediated proximal tubular transport.
- Published
- 2020
33. Pregnancy in Advanced Kidney Disease: Clinical Practice Considerations on a Challenging Combination
- Author
-
Albertien M. van Eerde, Rieke van der Graaf, Nine V A M Knoers, Franka E. van Reekum, A. Titia Lely, Jildau R Meinderts, Kitty W. M. Bloemenkamp, and Rozemarijn Snoek
- Subjects
Counseling ,medicine.medical_specialty ,AUTONOMY ,Decreased life expectancy ,INFORMATION ,Reproductive Techniques, Assisted ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,GUIDELINES ,Kidney ,Expert committee ,03 medical and health sciences ,0302 clinical medicine ,Life Expectancy ,Multidisciplinary approach ,Pregnancy ,Chronic kidney disease ,Prenatal Diagnosis ,medicine ,CKD ,Humans ,Genetic Testing ,Renal Insufficiency, Chronic ,Intensive care medicine ,Young female ,Genetic kidney disease ,Genetic testing ,Preimplantation genetic diagnostics ,RISK ,OUTCOMES ,medicine.diagnostic_test ,Clinical Practice: Research Article ,business.industry ,TRANSPLANTATION ,WOMEN ,medicine.disease ,Clinical Practice ,LIFE ,Pregnancy Complications ,PREECLAMPSIA ,Female ,business ,Kidney disease - Abstract
Background:Thanks to the advances in care, pregnancy is now attainable for the majority of young female CKD patients, although it is still a high-risk endeavor. Clinical decision-making in these cases is impacted by a myriad of factors, making (pre)pregnancy counseling a complex process. The complexities, further impacted by limited data and unknown risks regarding outcome, can cause discussions when deciding on the best care for a specific patient. Objectives:In this article, we provide an overview of the considerations and dilemmas we encounter in preconception counseling and offer our perspective on how to deal with them in daily clinical practice. Methods:The main topics we discuss in our counseling are (1) the high risk of pregnancy complications, (2) the risk of permanent CKD deterioration due to pregnancy and subsequent decreased life expectancy, (3) appropriate changes in renal medication, and (4) assisted reproduction, genetic testing, and prenatal or preimplantation genetic diagnostics. Results and Conclusions:In our clinic, we openly address moral dilemmas arising in clinical practice in pregnancy and CKD, both within the physician team and with the patient. We do this by ensuring an interpretive physician-patient interaction and shared decision-making, deliberating in a multidisciplinary setting and, if needed, with input from an expert committee.
- Published
- 2020
34. Modifier genes in SCN1A‐related epilepsy syndromes
- Author
-
Bobby P. C. Koeleman, Iris M de Lange, Ruben van 't Slot, Nine V A M Knoers, Marjan J. A. van Kempen, Eva H. Brilstra, Robert F Ernst, Isaac J. Nijman, Flip Mulder, and Anja C M Sonsma
- Subjects
0301 basic medicine ,Male ,DRAVET-SYNDROME ,VARIANTS ,030105 genetics & heredity ,Dravet ,Epilepsy ,modifier genes ,Exome ,SCN1A ,Child ,Genetics (clinical) ,Genetics ,SEVERE MYOCLONIC EPILEPSY ,MOUSE MODEL ,Middle Aged ,Phenotype ,Child, Preschool ,Cohort ,Original Article ,Female ,GEFS+ ,Adult ,lcsh:QH426-470 ,Adolescent ,PHENOTYPES ,Genomics ,Biology ,03 medical and health sciences ,medicine ,GEFS PLUS ,Humans ,Molecular Biology ,Gene ,Aged ,SPECTRUM ,Genes, Modifier ,DELETION ,Original Articles ,FRAMEWORK ,medicine.disease ,Minor allele frequency ,NAV1.1 Voltage-Gated Sodium Channel ,lcsh:Genetics ,030104 developmental biology ,Epilepsy syndromes ,epilepsy ,SCN1A MUTATION ,phenotypic variability ,Epileptic Syndromes ,Modifier Genes - Abstract
Background SCN1A is one of the most important epilepsy‐related genes, with pathogenic variants leading to a range of phenotypes with varying disease severity. Different modifying factors have been hypothesized to influence SCN1A‐related phenotypes. We investigate the presence of rare and more common variants in epilepsy‐related genes as potential modifiers of SCN1A‐related disease severity. Methods 87 patients with SCN1A‐related epilepsy were investigated. Whole‐exome sequencing was performed by the Beijing Genomics Institute (BGI). Functional variants in 422 genes associated with epilepsy and/or neuronal excitability were investigated. Differences in proportions of variants between the epilepsy genes and four control gene sets were calculated, and compared to the proportions of variants in the same genes in the ExAC database. Results Statistically significant excesses of variants in epilepsy genes were observed in the complete cohort and in the combined group of mildly and severely affected patients, particularly for variants with minor allele frequencies of, Relatively common variants in epilepsy genes may play a large role in modulating SCN1A‐related phenotypes. They may modify the phenotypes of both severely and mildly affected patients.
- Published
- 2020
35. Biallelic variants in POLR3GL cause endosteal hyperostosis and oligodontia
- Author
-
Sjors Middelkamp, Peter G.J. Nikkels, Marijn Créton, Nine V A M Knoers, Judith M. Vlaar, Paulien A Terhal, Jamila Ross, Jeroen W. Bos, Elsbeth S M Voskuil-Kerkhof, Rutger A.J. Nievelstein, Edwin Cuppen, and Koen L.I. van Gassen
- Subjects
Adult ,RNA Splicing ,CONSERVATION ,Monozygotic twin ,Biology ,Compound heterozygosity ,Osteochondrodysplasias ,RNA polymerase III ,Article ,03 medical and health sciences ,5S ribosomal RNA ,Transcription (biology) ,Loss of Function Mutation ,RNA-POLYMERASE III ,Genetics ,Journal Article ,Humans ,TRANSCRIPTION ,SCLEROSIS ,Gene ,CEREBELLAR HYPOPLASIA ,Genetics (clinical) ,Exome sequencing ,Anodontia ,POL III ,0303 health sciences ,SPECTRUM ,030305 genetics & heredity ,RNA ,RNA Polymerase III ,Syndrome ,COMPOUND HETEROZYGOUS MUTATIONS ,Phenotype ,Female ,HYPOMYELINATION ,4H SYNDROME - Abstract
RNA polymerase III (Pol III) is an essential 17-subunit complex responsible for the transcription of small housekeeping RNAs such as transfer RNAs and 5S ribosomal RNA. Biallelic variants in four genes (POLR3A, POLR3B, and POLR1C and POLR3K) encoding Pol III subunits have previously been found in individuals with (neuro-) developmental disorders. In this report, we describe three individuals with biallelic variants in POLR3GL, a gene encoding a Pol III subunit that has not been associated with disease before. Using whole exome sequencing in a monozygotic twin and an unrelated individual, we detected homozygous and compound heterozygous POLR3GL splice acceptor site variants. RNA sequencing confirmed the loss of full-length POLR3GL RNA transcripts in blood samples of the individuals. The phenotypes of the described individuals are mainly characterized by axial endosteal hyperostosis, oligodontia, short stature, and mild facial dysmorphisms. These features largely fit within the spectrum of phenotypes caused by previously described biallelic variants in POLR3A, POLR3B, POLR1C, and POLR3K. These findings further expand the spectrum of POLR3-related disorders and implicate that POLR3GL should be included in genetic testing if such disorders are suspected.
- Published
- 2020
36. Diagnostic Yield of Next-Generation Sequencing in Patients With Chronic Kidney Disease of Unknown Etiology
- Author
-
Liffert Vogt, Nine V A M Knoers, Martin H. de Borst, Mark Eijgelsheim, and Amber de Haan
- Subjects
0301 basic medicine ,medicine.medical_specialty ,lcsh:QH426-470 ,kidney disease ,Review ,Disease ,urologic and male genital diseases ,End stage renal disease ,genetic testing ,03 medical and health sciences ,0302 clinical medicine ,NEPHROTIC SYNDROME ,MONOGENIC CAUSE ,Genetics ,medicine ,Intensive care medicine ,CARDIOVASCULAR EVENTS ,Genetics (clinical) ,Exome sequencing ,Genetic testing ,diagnostic utility ,Kidney ,end-stage renal disease ,medicine.diagnostic_test ,CHALLENGES ,business.industry ,MUTATIONS ,MEDICINE ,GLOBAL BURDEN ,medicine.disease ,WHOLE-EXOME ,PREVALENCE ,lcsh:Genetics ,CONGENITAL-ANOMALIES ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Etiology ,Molecular Medicine ,business ,Nephrotic syndrome ,exome sequencing ,Kidney disease - Abstract
Advances in next-generation sequencing (NGS) techniques, including whole exome sequencing, have facilitated cost-effective sequencing of large regions of the genome, enabling the implementation of NGS in clinical practice. Chronic kidney disease (CKD) is a major contributor to global burden of disease and is associated with an increased risk of morbidity and mortality. CKD can be caused by a wide variety of primary renal disorders. In about one in five CKD patients, no primary renal disease diagnosis can be established. Moreover, recent studies indicate that the clinical diagnosis may be incorrect in a substantial number of patients. Both the absence of a diagnosis or an incorrect diagnosis can have therapeutic implications. Genetic testing might increase the diagnostic accuracy in patients with CKD, especially in patients with unknown etiology. The diagnostic utility of NGS has been shown mainly in pediatric CKD cohorts, while emerging data suggest that genetic testing can also be a valuable diagnostic tool in adults with CKD. In addition to its implications for unexplained CKD, NGS can contribute to the diagnostic process in kidney diseases with an atypical presentation, where it may lead to reclassification of the primary renal disease diagnosis. So far, only a few studies have reported on the diagnostic yield of NGS-based techniques in patients with unexplained CKD. Here, we will discuss the potential diagnostic role of gene panels and whole exome sequencing in pediatric and adult patients with unexplained and atypical CKD.
- Published
- 2019
37. NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD
- Author
-
Zhongyang Zhang, Rozemarijn Snoek, Albertien M. van Eerde, Martin H. de Borst, Ajay K. Israni, Edith D.J. Peters, Pamala A. Jacobson, Peter J. Conlon, Roman Reindl-Schwaighofer, Jessica van Setten, Barbara Murphy, Nine V A M Knoers, Brendan J. Keating, Ke Hao, Ondrej Viklicky, Bert van der Zwaag, Weijia Zhang, Harold Snieder, Caragh P. Stapleton, Roslyn B. Mannon, William S. Oetting, Andreas Heinzl, Rainer Oberbauer, Stephan J. L. Bakker, Arthur J. Matas, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), and Life Course Epidemiology (LCE)
- Subjects
Adult ,0301 basic medicine ,medicine.medical_specialty ,RENAL-FAILURE ,government.form_of_government ,030232 urology & nephrology ,human genetics ,urologic and male genital diseases ,End stage renal disease ,03 medical and health sciences ,0302 clinical medicine ,Clinical Research ,Nephronophthisis ,Internal medicine ,LOCUS ,medicine ,Humans ,Juvenile nephronophthisis ,Copy-number variation ,cystic kidney ,Adaptor Proteins, Signal Transducing ,Genetic testing ,Cystic kidney ,end-stage renal disease ,IDENTIFICATION ,medicine.diagnostic_test ,business.industry ,Membrane Proteins ,genetic renal disease ,KIDNEY-DISEASE ,General Medicine ,Kidney Diseases, Cystic ,medicine.disease ,JUVENILE NEPHRONOPHTHISIS ,Transplantation ,Cytoskeletal Proteins ,030104 developmental biology ,Nephrology ,government ,Kidney Failure, Chronic ,business ,Gene Deletion ,transplantation ,Kidney disease - Abstract
Background Nephronophthisis (NPH) is the most prevalent genetic cause for ESRD in children. However, little is known about the prevalence of NPH in adult-onset ESRD. Homozygous full gene deletions of the NPHP1 gene encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous NPHP1 full gene deletions in adult-onset ESRD.Methods Adult renal transplant recipients from five cohorts of the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) underwent single-nucleotide polymorphism genotyping. After quality control, we determined autosomal copy number variants (such as deletions) on the basis of median log2 ratios and B-allele frequency patterns. The findings were independently validated in one cohort. Patients were included in the analysis if they had adult-onset ESRD, defined as start of RRT at >= 18 years old.Results We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous NPHP1 deletions. No donor controls showed homozygosity for this deletion. Median age at ESRD onset was 30 (range, 18-61) years old for patients with NPH, with 54% of patients age >= 30 years old. Notably, only three (12%) patients were phenotypically classified as having NPH, whereas most patients were defined as having CKD with unknown etiology (n=11; 42%).Conclusions Considering that other mutation types in NPHP1 or mutations in other NPH-causing genes were not analyzed, NPH is a relatively frequent monogenic cause of adult-onset ESRD. Because 88% of patients had not been clinically diagnosed with NPH, wider application of genetic testing in adult-onset ESRD may be warranted.
- Published
- 2018
38. Sox11 gene disruption causes congenital anomalies of the kidney and urinary tract (CAKUT): SOX11 and CAKUT
- Author
-
Franz Schaefer, Ernie M.H.F. Bongers, Mansoureh Tabatabaei, Véronique Lefebvre, Kirsten Y. Renkema, Helen McNeill, Wout F.J. Feitz, Haroun Dhib, Herbert Schulz, Michael Wegner, Vladimir M. Kozlov, Elisabeth Sock, Filippo Massa, Yasmine Neirijnck, Albertien M. van Eerde, Nine V A M Knoers, Andreas Schedl, Antoine Reginensi, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), University Medical Center [Utrecht], Radboud University Medical Center [Nijmegen], Cleveland Clinic, Heidelberg University, University of Cologne, Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), ANR-09-GENO-027-01, ANR-11-LABX-0028-01, ARC (SL22020605297), Fondation de la Recherche Medicale (FRM, ING20160435020), European Project: 305608,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EURENOMICS(2012), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
- Subjects
0301 basic medicine ,Sox11 ,Kidney development ,Nephron ,Biology ,Nephrogenic Cord ,medicine.disease_cause ,Duplex Kidney ,03 medical and health sciences ,Transactivation ,All institutes and research themes of the Radboud University Medical Center ,medicine ,Glial cell line-derived neurotrophic factor ,duplex kidneys ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,CAKUT ,Mutation ,Kidney ,nephron ,kidney induction ,030104 developmental biology ,medicine.anatomical_structure ,Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] ,Nephrology ,Cancer research ,biology.protein ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
International audience; Congenital abnormalities of the kidney and the urinary tract (CAKUT) belong to the most common birth defectsin human, but the molecular basis for the majority of CAKUT patients remains unknown. Here we show thatthe transcription factor SOX11 is a crucial regulator of kidney development. SOX11 is expressed in bothmesenchymal and epithelial components of the early kidney anlagen. Deletion of Sox11 in mice causes anextension of the domain expressing Gdnf within rostral regions of the nephrogenic cord and results in duplexkidney formation. On the molecular level SOX11 directly binds and regulates a locus control region of theprotocadherin B cluster. At later stages of kidney development, SOX11 becomes restricted to the intermediatesegment of the developing nephron where it is required for the elongation of Henle’s loop. Finally, mutationanalysis in a cohort of patients suffering from CAKUT identified a series of rare SOX11 variants, one of whichinterferes with the transactivation capacity of the SOX11 protein. Taken together these data demonstrate akey role for SOX11 in normal kidney development and may suggest that variants in this gene predispose toCAKUT in humans
- Published
- 2018
39. Further delineation of the GDF6 related multiple synostoses syndrome
- Author
-
Ralph J. B. Sakkers, Nine V A M Knoers, Paulien A Terhal, Gijs van Haaften, Lucienne Speleman, Ans M.W. van den Ouweland, Nienke E. Verbeek, Rutger A.J. Nievelstein, and Clinical Genetics
- Subjects
0301 basic medicine ,Male ,Hearing loss ,BMP/TGFß signaling ,DNA Mutational Analysis ,Tarsal-carpal fusion ,030105 genetics & heredity ,Growth Differentiation Factor 6 ,Bioinformatics ,Adult age ,03 medical and health sciences ,Noggin ,Multiple synostoses syndrome ,medicine ,Genetics ,Journal Article ,Humans ,Genetics(clinical) ,Abnormalities, Multiple ,Child ,Genetics (clinical) ,Genetic Association Studies ,Aged ,business.industry ,GDF6 ,Multiple synostoses ,Synostosis ,medicine.disease ,Pedigree ,Radiography ,030104 developmental biology ,Phenotype ,Child, Preschool ,Mutation (genetic algorithm) ,Mutation ,Otosclerosis ,Female ,medicine.symptom ,business - Abstract
A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome.
- Published
- 2018
40. The von Hippel-Lindau Gene Is Required to Maintain Renal Proximal Tubule and Glomerulus Integrity in Zebrafish Larvae
- Author
-
Emile E. Voest, Stefan Schulte-Merker, Ellen van Rooijen, Freek van Eeden, Ive Logister, Nine V A M Knoers, Glenn van de Hoek, Rachel H. Giles, and Henry Ajzenberg
- Subjects
0301 basic medicine ,endocrine system diseases ,biology ,business.industry ,Endocytic cycle ,Glomerulus (kidney) ,urologic and male genital diseases ,medicine.disease ,biology.organism_classification ,female genital diseases and pregnancy complications ,Pronephros ,Cell biology ,03 medical and health sciences ,Clear cell renal cell carcinoma ,030104 developmental biology ,medicine.anatomical_structure ,Endocytic vesicle ,Tubule ,Renal pathology ,medicine ,business ,neoplasms ,Zebrafish - Abstract
Background: von Hippel-Lindau (VHL) disease is characterized by the development of benign and malignant tumours in many organ systems, including renal cysts and clear cell renal cell carcinoma. It is not completely understood what underlies the development of renal pathology, and the use of murine Vhl models has been challenging due to limitations in disease conservation. We previously described a zebrafish model bearing inactivating mutations in the orthologue of the human VHL gene. Methods: We used histopathological and functional assays to investigate the pronephric and glomerular developmental defects in vhl mutant zebrafish, supported by human cell culture assays. Results: Here, we report that vhl is required to maintain pronephric tubule and glomerulus integrity in zebrafish embryos. vhl mutant glomeruli are enlarged, cxcr4a+ capillary loops are dilated and the Bowman space is widened. While we did not observe pronephric cysts, the cells of the proximal convoluted and anterior proximal straight tubule are enlarged, periodic acid schiff (PAS) and Oil Red O positive, and display a clear cytoplasm after hematoxylin and eosine staining. Ultrastructural analysis showed the vhl–/– tubule to accumulate large numbers of vesicles of variable size and electron density. Microinjection of the endocytic fluorescent marker AM1–43 in zebrafish embryos revealed an accumulation of endocytic vesicles in the vhl mutant pronephric tubule, which we can recapitulate in human cells lacking VHL. Conclusions: Our data indicates that vhl is required to maintain pronephric tubule and glomerulus integrity during zebrafish development, and suggests a role for VHL in endocytic vesicle trafficking.
- Published
- 2018
41. Photosensitivity in Dravet syndrome is under-recognized and related to prognosis
- Author
-
Anja C M Sonsma, Al W. de Weerd, Dorothée G.A. Kasteleijn-Nolst Trenité, Nine V A M Knoers, Frans S. S. Leijten, Merel Wassenaar, Thea Gutter, W. Boudewijn Gunning, Jolien S. van Campen, Nienke E. Verbeek, Willy P. J. Spetgens, and Eva H. Brilstra
- Subjects
0301 basic medicine ,Male ,Pathology ,Pediatrics ,Photic Stimulation ,Epilepsies, Myoclonic ,Electroencephalography ,Epilepsies ,Epilepsies, Myoclonic/complications ,0302 clinical medicine ,Reflex/diagnosis ,Intellectual disability ,Prevalence ,SCN1A ,Intermittent photic stimulation ,Child ,medicine.diagnostic_test ,Epilepsy, Reflex/diagnosis ,Visual sensitivity ,Sensory Systems ,Neurology ,Child, Preschool ,Female ,medicine.medical_specialty ,Adolescent ,Myoclonic/complications ,PPR ,Epilepsy, Reflex ,03 medical and health sciences ,Self-induction ,Dravet syndrome ,Pattern stimulation ,Physiology (medical) ,medicine ,Journal Article ,Humans ,Preschool ,Photoparoxysmal EEG response ,Epilepsy ,NAV1.1 Voltage-Gated Sodium Channel/genetics ,business.industry ,Self induction ,Infant ,medicine.disease ,NAV1.1 Voltage-Gated Sodium Channel ,030104 developmental biology ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Objective: To detect determinants for photoparoxysmal EEG response (PPR) in SCN1A -related Dravet syndrome (DS). Methods: Data were studied from nationwide medical histories and EEGs of DS-patients ( n =53; 31 males, age 2–19years). Detailed questionnaires on visual stimuli were completed by parents ( n =49). Results: PPR was found in 22 patients (42%; median age 1.25yr), and repeatedly in 17%. PPR (17% of 249 intermittent photic stimulation (IPS)-EEGs) occurred more often with optimal IPS protocols (OR 2.11 [95%CI 1.09–4.13]) and in EEGs showing spontaneous epileptiform abnormalities (OR 5.08 [95%CI 2.05–12.55]). PPR-positive patients tended to be younger at first ( p =0.072) and second seizure ( p =0.049), showed severe intellectual disability ( p =0.042), and had more often spontaneous occipital epileptiform abnormalities ( p Clinical sensitivity was reported in medical files in 22% of patients and by parents in 43% (self-induction 24%). Clinical or EEG proven visual sensitivity was detected in 65% of cases. Conclusions: Sensitivity to visual stimuli is very common in DS and more often noticed by parents than confirmed by EEG. Detection of PPR improves with repetitive tests using accurate IPS protocols. Significance: Photosensitivity is an important feature in DS and seems to be a marker of the severity of the disorder. Therefore repeated standardized IPS should be encouraged.
- Published
- 2017
42. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
- Author
-
Martin Konrad, David H. Ellison, Shih-Hua Lin, Rosa Vargas-Poussou, Anne Blanchard, Olivier Devuyst, Detlef Bockenhauer, Davide Bolignano, Lorenzo A. Calò, Nine V A M Knoers, Fiona E. Karet Frankl, Etienne Cosyns, University of Zurich, Devuyst, Olivier, Blanchard, Anne [0000-0002-0815-0586], Bolignano, Davide [0000-0003-3032-245X], Ellison, David H [0000-0003-2915-265X], Apollo - University of Cambridge Repository, CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University College of London [London] (UCL), Great Ormond Street Hospital for Children [London] (GOSH), Consiglio Nazionale delle Ricerche / National Research Council [Calabria, Italy] (CNR), Universita degli Studi di Padova, Wanze [Belgium], Universität Zürich [Zürich] = University of Zurich (UZH), Oregon Health and Science University [Portland] (OHSU), University of Cambridge [UK] (CAM), Cambridge University Hospitals - NHS (CUH), University Medical Center [Utrecht], University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), National Taiwan University [Taiwan] (NTU), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Padova = University of Padua (Unipd), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), and HULOT, Jean-Sébastien
- Subjects
Calcium/urine ,Sodium Chloride, Dietary/therapeutic use ,Consensus Development Conferences as Topic ,030232 urology & nephrology ,Anti-Inflammatory Agents ,Angiotensin-Converting Enzyme Inhibitors ,Disease ,030204 cardiovascular system & hematology ,Sodium Chloride ,thiazide-sensitive sodium-chloride cotransporter ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,10052 Institute of Physiology ,0302 clinical medicine ,Gitelman Syndrome/complications ,Diagnosis ,salt-losing tubulopathy ,Medicine ,Potassium/administration & dosage ,Magnesium ,Solute Carrier Family 12, Member 3 ,Ultrasonography ,2727 Nephrology ,Magnesium/administration & dosage ,medicine.diagnostic_test ,Anti-Inflammatory Agents, Non-Steroidal ,Dietary/therapeutic use ,Bartter Syndrome/blood ,Angiotensin Receptor Antagonists/therapeutic use ,3. Good health ,Angiotensin-Converting Enzyme Inhibitors/therapeutic use ,Chondrocalcinosis/etiology ,Phenotype ,Nephrology ,Practice Guidelines as Topic ,Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ,medicine.symptom ,Gitelman Syndrome ,medicine.medical_specialty ,Non-Steroidal/therapeutic use ,Solute Carrier Family 12 ,Chloride Channels/genetics ,610 Medicine & health ,Chondrocalcinosis ,Hypokalemia ,Hypocalciuria ,Diagnosis, Differential ,03 medical and health sciences ,hypomagnesemia ,Angiotensin Receptor Antagonists ,Rare Diseases/genetics ,Rare Diseases ,Tubulopathy ,Chloride Channels ,Journal Article ,Humans ,Genetic Testing ,Salt intake ,Sodium Chloride, Dietary ,Intensive care medicine ,Genetic testing ,business.industry ,Bartter Syndrome ,Gitelman syndrome ,medicine.disease ,[SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,hypokalemic metabolic alkalosis ,Differential ,Member 3/genetics ,Dietary Supplements ,Mutation ,Hypokalemia/blood ,Potassium ,Quality of Life ,570 Life sciences ,biology ,Calcium ,SLC12A3 ,Differential diagnosis ,Solute Carrier Family 12, Member 3/genetics ,business ,Kidney disease - Abstract
International audience; Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.
- Published
- 2017
- Full Text
- View/download PDF
43. Impact of next generation sequencing on our understanding of CAKUT
- Author
-
Anukrati Nigam, Nine V A M Knoers, and Kirsten Y. Renkema
- Subjects
0301 basic medicine ,Etiology ,Disease ,Computational biology ,Biology ,Kidney ,DNA sequencing ,Recurrence risk ,03 medical and health sciences ,0302 clinical medicine ,Next generation sequencing ,Genetics ,Animals ,Humans ,Genetic Predisposition to Disease ,Genetic Association Studies ,CAKUT ,Vesico-Ureteral Reflux ,Genetic heterogeneity ,Gene Expression Regulation, Developmental ,High-Throughput Nucleotide Sequencing ,Cell Biology ,Kidney disease ,Disease gene identification ,Penetrance ,030104 developmental biology ,Urogenital Abnormalities ,Mutation ,Identification (biology) ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Congenital abnormalities of the kidney and urinary tract (CAKUT) form the leading cause of pediatric end-stage renal disease. Knowledge on the molecular mechanisms that underlie CAKUT leads to the improvement of DNA diagnostics and counseling regarding prognosis and recurrence risk estimation for CAKUT patients and their relatives. Implementation of next generation sequencing in research and diagnostic settings has led to the identification of the molecular basis of many developmental diseases. In this review, we summarize the efforts on next generation sequencing in CAKUT research and we discuss how next generation sequencing added to our understanding of CAKUT genetics. Although next generation sequencing has certainly proven to be a game changer in the field of disease gene identification and novel CAKUT-causing gene variants have been identified, most CAKUT cases still remain unsolved. Occurring with genetic and phenotypic heterogeneity along with incomplete penetrance, the identification of CAKUT etiology poses many challenges. We see great potential for combined -omics approaches that include next generation sequencing in the identification of CAKUT-specific biomarkers, which is necessary to optimize the care for CAKUT patients.
- Published
- 2019
44. Influence of common SCN1A promoter variants on the severity of SCN1A-related phenotypes
- Author
-
Boudewijn Gunning, Flip Mulder, Mark McCormack, Ruben van 't Slot, Anja C M Sonsma, Iris M de Lange, Wout J. Weuring, Eva H. Brilstra, Nine V A M Knoers, Carolien G.F. de Kovel, Bobby P. C. Koeleman, Lisette J. J. M. van Gemert, and Marjan J. A. van Kempen
- Subjects
Adult ,Male ,GEFS+ ,medicine.medical_specialty ,Adolescent ,lcsh:QH426-470 ,Biology ,Polymorphism, Single Nucleotide ,Severity of Illness Index ,Dravet ,Variable Expression ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Genes, Reporter ,Cell Line, Tumor ,Molecular genetics ,medicine ,Genetics ,Humans ,Genomic medicine ,Genetics(clinical) ,SCN1A ,Child ,Promoter Regions, Genetic ,Molecular Biology ,Alleles ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Epilepsy ,promoter ,fungi ,Original Articles ,Phenotype ,NAV1.1 Voltage-Gated Sodium Channel ,lcsh:Genetics ,variable expression ,Haplotypes ,Child, Preschool ,Original Article ,5' Untranslated Regions ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
BACKGROUND: Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants.METHODS: Five different SCN1A promoter-haplotypes were functionally assessed in SH-SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter-region of their unaffected allele were investigated.RESULTS: All non-wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter-region (65%-80%, p = 0.039-0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter-haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes.CONCLUSION: The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter-haplotypes.
- Published
- 2019
45. Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome
- Author
-
Jack F.M. Wetzels, Monika Mozere, Nine V A M Knoers, Chris Cheshire, Lucy Jenkins, Daljit Hothi, Horia Stanescu, Jeroen Nauta, Robert Kleta, Enriko Klootwijk, Matthew J. Stubbs, A S Abeyagunawardena, Adebowale Adeyemo, Elena Levtchenko, Rasheed Gbadegesin, Lighta Godinho, Detlef Bockenhauer, Nynke Teeninga, Sherif M. El-Desoky, Mark Kristiansen, Sanjana Gupta, Vaksha Patel, Naomi Issler, Mohamed A. Shalaby, Jameela A. Kari, Daniel P. Gale, Randula Ranawaka, Hazel Webb, Aoife M. Waters, Kjell Tullus, Adam P. Levine, Stephanie Dufek, Richard S. Trompeter, Shenal Thalgahagoda, Nicholas J.A Webb, and Pediatrics
- Subjects
Male ,Nephrotic Syndrome ,Databases, Factual ,Genotype ,Quantitative Trait Loci ,Genome-wide association study ,Disease ,Human leukocyte antigen ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Androgen-Binding Protein ,HLA-DQ alpha-Chains ,CALHM6 ,Epitopes ,SSNS ,medicine ,Odds Ratio ,SNP ,GWAS ,HLA-DQ beta-Chains ,Humans ,Genetic Predisposition to Disease ,FAM26F ,Child ,Alleles ,Genetic association ,Autoimmune disease ,Membrane Glycoproteins ,General Medicine ,Immune dysregulation ,medicine.disease ,HLA ,Basic Research ,Nephrology ,Immune System ,Immunology ,Expression quantitative trait loci ,Female ,Steroids ,Calcium Channels ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,Peptides ,Genome-Wide Association Study ,HLA-DRB1 Chains - Abstract
BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance. METHODS: In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls. RESULTS: The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10-43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10-17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6. CONCLUSIONS: Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS. ispartof: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY vol:30 issue:8 pages:1375-1384 ispartof: location:United States status: published
- Published
- 2019
46. Importance of Genetic Diagnostics in Adult-Onset Focal Segmental Glomerulosclerosis
- Author
-
Hannah M E Kruis, Arjan D. van Zuilen, Rozemarijn Snoek, Maarten B. Rookmaaker, Nine V A M Knoers, Bert van der Zwaag, Liesbeth A van Gils-Verrij, Albertien M. van Eerde, Roel Goldschmeding, and Tri Q. Nguyen
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,urogenital system ,030232 urology & nephrology ,Disease ,Case Reports ,030204 cardiovascular system & hematology ,HNF1B ,Bioinformatics ,medicine.disease ,urologic and male genital diseases ,female genital diseases and pregnancy complications ,03 medical and health sciences ,INF2 ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,medicine ,Experimental Nephrology and Genetics: Case Study of Genetic Interest ,In patient ,Histopathology ,Family history ,business ,Genetic testing - Abstract
Focal segmental glomerulosclerosis (FSGS) is a histological pattern of podocyte and glomerulus injury. FSGS can be primary and secondary to other diseases or due to a genetic cause. Strikingly, genetic causes for adult-onset FSGS are often overlooked, likely because identifying patients with genetic forms of FSGS based on clinical presentation and histopathology is difficult. Yet diagnosing genetic FSGS does not only have implications for prognostication and therapy but also for family and family planning. In this case series, we present 3 adult patients who presented with advanced renal disease with the histological picture of FSGS and proved to have a genetic cause of the disease, namely, variants in INF2, COL4A4 and HNF1B, respectively. We show the possibilities of identifying genetic FSGS based on clinical clues of a positive family history, early age at onset of disease, and/or severe therapy-resistant disease. We discuss ways to select the method of genetic testing for individual patients. Finally, we examine how the judicious use of genetic investigations can obviate potential harmful diagnostic procedures and direct clinical decisions in patients and their relatives.
- Published
- 2019
47. Cantú syndrome: Findings from 74 patients in the International Cantú Syndrome Registry
- Author
-
Jin-Moo Lee, Gautam K. Singh, Helen I. Roessler, Kathleen Shields, Conor McClenaghan, Mieke M. van Haelst, Sarah F. Smithson, Edwin P. Kirk, Karen Duran, Dorothy K. Grange, Ingrid Scurr, Colin G. Nichols, Gijs van Haaften, Nine V A M Knoers, Maria S. Remedi, Amsterdam Reproduction & Development (AR&D), Human genetics, and Amsterdam Neuroscience - Complex Trait Genetics
- Subjects
0301 basic medicine ,Hypertrichosis ,Cantú syndrome ,Adult ,Male ,medicine.medical_specialty ,Polyhydramnios ,Adolescent ,Cardiomegaly ,030105 genetics & heredity ,Osteochondrodysplasias ,Article ,ABCC9 ,03 medical and health sciences ,Young Adult ,Internal medicine ,Ductus arteriosus ,Genetics ,medicine ,Humans ,Registries ,Child ,Genetics (clinical) ,business.industry ,Facies ,medicine.disease ,Penetrance ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,Migraine ,Cardiology ,Female ,Headaches ,medicine.symptom ,business - Abstract
Cantú syndrome (CS), first described in 1982, is caused by pathogenic variants in ABCC9 and KCNJ8, which encode the regulatory and pore forming subunits of ATP-sensitive potassium (K(ATP)) channels, respectively. Multiple case reports of affected individuals have described the various clinical features of CS, but systematic studies are lacking. To define the effects of genetic variants on CS phenotypes and clinical outcomes, we have developed a standardized REDCap-based registry for CS. We report phenotypic features and associated genotypes on 74 CS subjects, with confirmed ABCC9 variants in 72 of the individuals. Hypertrichosis and a characteristic facial appearance are present in all individuals. Polyhydramnios during fetal life, hyperflexibility, edema, patent ductus arteriosus (PDA), cardiomegaly, dilated aortic root, vascular tortuosity of cerebral arteries, and migraine headaches are common features, although even with this large group of subjects, there is incomplete penetrance of CS-associated features, without clear correlation to genotype.
- Published
- 2019
48. Identification of human D lactate dehydrogenase deficiency
- Author
-
Karen Duran, Johanna C. van Alfen, Paolo Bosco, Judith J.M. Jans, Paulien A Terhal, Saskia N. van der Crabben, Gepke Visser, Koen L.I. van Gassen, Markus J. van Roosmalen, Karin Geleijns, Tom J. de Koning, Nanda M. Verhoeven-Duif, Marinus Duran, Francesco Calì, Monique G.M. de Sain-van der Velden, Glen R. Monroe, Klaske D. Lichtenbelt, Bart G. Koot, Sabine A. Fuchs, Marlies Oostendorp, Johan Gerrits, Nine V A M Knoers, Albertien M. van Eerde, Mirjam van Aalderen, Sanne M C Savelberg, Federico Tessadori, Jeroen Bakkers, Gijs van Haaften, Human genetics, Pediatric surgery, Hubrecht Institute for Developmental Biology and Stem Cell Research, Human Genetics, Paediatric Gastroenterology, AGEM - Digestive immunity, AGEM - Re-generation and cancer of the digestive system, ARD - Amsterdam Reproduction and Development, and Movement Disorder (MD)
- Subjects
Male ,0301 basic medicine ,General Physics and Astronomy ,02 engineering and technology ,Consanguinity ,Loss of Function Mutation ,Non-U.S. Gov't ,lcsh:Science ,Zebrafish ,Acidosis ,Multidisciplinary ,ABNORMALITIES ,Research Support, Non-U.S. Gov't ,Homozygote ,ANIRIDIA ,021001 nanoscience & nanotechnology ,Short bowel syndrome ,Phenotype ,D-lactate dehydrogenase ,Medical genetics ,Acidosis, Lactic ,medicine.symptom ,0210 nano-technology ,Spasms, Infantile ,Adult ,Short Bowel Syndrome ,EXPRESSION ,medicine.medical_specialty ,DISORDERS ,Science ,Biology ,METABOLISM ,Research Support ,DIAGNOSIS ,Article ,General Biochemistry, Genetics and Molecular Biology ,Diagnosis, Differential ,03 medical and health sciences ,Internal medicine ,Journal Article ,medicine ,Animals ,Humans ,Lactic Acid ,Lactate Dehydrogenases ,Gene ,D-LACTIC ACIDOSIS ,PURIFICATION ,Wild type ,Infant ,General Chemistry ,medicine.disease ,biology.organism_classification ,ACIDS ,GENE ,030104 developmental biology ,Endocrinology ,lcsh:Q - Abstract
Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this with the identification of two different homozygous variants resulting in enzymatic loss-of-function in LDHD, encoding lactate dehydrogenase D, in two unrelated patients with elevated D-lactate urinary excretion and plasma concentrations. We establish the role of LDHD by demonstrating that LDHD loss-of-function in zebrafish results in increased concentrations of D-lactate. D-lactate levels are rescued by wildtype LDHD but not by patients’ variant LDHD, confirming these variants’ loss-of-function effect. This work provides the first in vivo evidence that LDHD is responsible for human D-lactate metabolism. This broadens the differential diagnosis of D-lactic acidosis, an increasingly recognized complication of short bowel syndrome with unpredictable onset and severity. With the expanding incidence of intestinal resection for disease or obesity, the elucidation of this metabolic pathway may have relevance for those patients with D-lactic acidosis., D-lactic acidosis typically occurs in the context of short bowel syndrome; excess D-lactate is produced by intestinal bacteria. Here, the authors identify two point mutations in the human lactate dehydrogenase D (LDHD) gene that cause enzymatic loss of function and are associated with elevated plasma D-lactate.
- Published
- 2019
49. Changes in the urinary extracellular vesicle proteome are associated with nephronophthisis-related ciliopathies
- Author
-
Marc R. Lilien, Kirsten Y. Renkema, Ernie M.H.F. Bongers, Thang V. Pham, Irene V. Bijnsdorp, Connie R. Jimenez, Jaco C. Knol, Rachel H. Giles, Marijn Stokman, Nine V A M Knoers, Tim Schelfhorst, Sander R. Piersma, Urology, Medical oncology laboratory, AGEM - Re-generation and cancer of the digestive system, Amsterdam Neuroscience - Neurodegeneration, and AII - Inflammatory diseases
- Subjects
Adult ,Male ,Proteomics ,0301 basic medicine ,Adolescent ,Proteome ,Biophysics ,PRIMARY CILIA ,Renal ciliopathy ,Urine ,Biology ,Biochemistry ,Extracellular Vesicles ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Nephronophthisis ,MARKERS ,medicine ,Humans ,Biomarker discovery ,Child ,LABEL-FREE ,IDENTIFICATION ,030102 biochemistry & molecular biology ,MUTATIONS ,KIDNEY-DISEASE ,Biomarker ,Extracellular vesicle ,Kidney Diseases, Cystic ,medicine.disease ,Actin cytoskeleton ,BIOMARKER DISCOVERY ,Ciliopathies ,Cell biology ,Ciliopathy ,TARGET ,030104 developmental biology ,Kidney Failure, Chronic ,Female ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Extracellular matrix organization - Abstract
Nephronophthisis is one of the leading genetic causes of end-stage renal disease in childhood. Early diagnostics and prognostics for nephronophthisis are currently limited. We aimed to identify non-invasive protein biomarkers for nephronophthisis in urinary extracellular vesicles. Extracellular vesicles were isolated from urine of 12 patients with a nephronophthisis-related ciliopathy and 12 age- and gender-matched controls, followed by in-depth label-free LC-MS/MS proteomics analysis of gel fractionated extracellular vesicle proteins. Supervised cluster analysis of proteomic profiles separated patients from controls. We identified 156 differentially expressed proteins with fold change ≥4 in patients compared to controls (P
- Published
- 2019
50. Importance of reliable variant calling and clear phenotyping when reporting on gene panel testing in renal disease
- Author
-
Rozemarijn Snoek, Albertien M. van Eerde, and Nine V A M Knoers
- Subjects
medicine.diagnostic_test ,business.industry ,030232 urology & nephrology ,High-Throughput Nucleotide Sequencing ,Disease ,030204 cardiovascular system & hematology ,medicine.disease ,Bioinformatics ,Pedigree ,03 medical and health sciences ,0302 clinical medicine ,Nephrology ,Gene panel ,medicine ,Humans ,Kidney Diseases ,Genetic Testing ,business ,Selection (genetic algorithm) ,Genetic testing ,Kidney disease - Abstract
Genetic testing in kidney disease has been gaining more attention in recent years as an important diagnostic tool. Especially in selected cases, genetic testing can be a first mode of diagnostics in various renal diseases. Mallett et al. are the first to report on the overall diagnostic yield of targeted gene panel testing in familial kidney disease, both in pediatric and adult cases. In this commentary we discuss the importance of a clear gene panel design, with an up-to-date enrichment offering sufficient coverage for each gene, and a validated pipeline for variant calling. We also emphasize the necessity of detailed phenotyping, including a pedigree, as a critical factor for gene panel selection and variant interpretation.
- Published
- 2017
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.