[Show abstract][Hide abstract] ABSTRACT: The advent of next-generation sequencing technologies has enabled genetic nephrology research to move beyond single gene analysis to the simultaneous investigation of hundreds of genes and entire pathways. These new sequencing approaches have been used to identify and characterize causal factors that underlie inherited heterogeneous kidney diseases such as nephronophthisis and congenital anomalies of the kidney and urinary tract. In this Review, we describe the development of next-generation sequencing in basic and clinical research and discuss the implementation of this novel technology in routine patient management. Widespread use of targeted and nontargeted approaches for gene identification in clinical practice will require consistent phenotyping, appropriate disease modelling and collaborative efforts to combine and integrate data analyses. Next-generation sequencing is an exceptionally promising technique that has the potential to improve the management of patients with inherited kidney diseases. However, identifying the molecular mechanisms that lead to renal developmental disorders and ciliopathies is difficult. A major challenge in the near future will be how best to integrate data obtained using next-generation sequencing with personalized medicine, including use of high-throughput disease modelling as a tool to support the clinical diagnosis of kidney diseases.
[Show abstract][Hide abstract] ABSTRACT: At least 10% of adults and nearly all children who receive renal-replacement therapy have an inherited kidney disease. These patients rarely die when their disease progresses and can remain alive for many years because of advances in organ-replacement therapy. However, these disorders substantially decrease their quality of life and have a large effect on health-care systems. Since the kidneys regulate essential homoeostatic processes, inherited kidney disorders have multisystem complications, which add to the usual challenges for rare disorders. In this review, we discuss the nature of rare inherited kidney diseases, the challenges they pose, and opportunities from technological advances, which are well suited to target the kidney. Mechanistic insights from rare disorders are relevant for common disorders such as hypertension, kidney stones, cardiovascular disease, and progression of chronic kidney disease.
[Show abstract][Hide abstract] ABSTRACT: During recent years our understanding of the pathogenesis of microcytic inherited anemias has gained from the identification of several genes and proteins involved in systemic and cellular iron metabolism and heme syntheses. Numerous case reports illustrate that the implementation of these novel molecular discoveries in clinical practice has increased our understanding of the presentation, diagnosis and management of these diseases. Integration of these insights in daily clinical practice will reduce delays in time to establish a proper diagnosis, invasive and/or costly diagnostic tests and unnecessary or even detrimental treatments. In order to assist the clinician, we developed an evidence-based multidisciplinary guideline on the management of rare microcytic anemias due to genetic disorders of iron metabolism and heme synthesis. These genetic disorders may present at all ages and therefore this guideline is relevant for pediatricians as well as clinicians treating adults. This article summarizes these clinical practice guideline and includes i) background on pathogenesis, ii) conclusions and recommendations and iii) a diagnostic flow chart to facilitate its use in the clinical setting.
[Show abstract][Hide abstract] 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.
PLoS ONE 01/2014; 9(7):e102065. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: X-linked sideroblastic anemia (XLSA) is the most common form of congenital sideroblastic anemia. In affected males, it is uniformly associated with partial loss-of-function missense mutations in the erythroid-specific heme biosynthesis protein 5-aminolevulinate synthase 2 (ALAS2). Here, we report five families with XLSA due to mutations in a GATA transcription factor binding site located in a transcriptional enhancer element in intron 1 of the ALAS2 gene. As such, this study defines a new class of mutations that should be evaluated in patients undergoing genetic testing for a suspected diagnosis of XLSA.
American Journal of Hematology 10/2013; · 4.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome.Methods and resultsClinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. CONCLUSIONS: This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.
[Show abstract][Hide abstract] ABSTRACT: In the last decade, an overwhelming number of genetic aberrations have been discovered and linked to the development of treatment for cancer. With the rapid advancement of next-generation sequencing (NGS) techniques, it is expected that large-scale DNA analyses will increasingly be used to select patients for treatment with specific anticancer agents. Personalizing cancer treatment has many advantages, but sequencing germline DNA as reference material for interpreting cancer genetics may have consequences that extend beyond providing cancer care for an individual patient. In sequencing germline DNA, mutations may be encountered that are associated with increased susceptibility not only to hereditary cancer syndromes but also to other diseases; in those cases, disclosing germline data could be clinically relevant and even lifesaving. In the context of personal autonomy, it is necessary to develop an ethical and legal framework for how to deal with identified hereditary disease susceptibilities and how to return the data to patients and their families. Because clear legislation is lacking, we need to establish guidelines on disclosure of genetic information and, in the process, we need to balance privacy issues with the potential advantages and drawbacks of sharing genetic data with patients and their relatives. Importantly, a strong partnership with patients is critical for understanding how to maximize the translation of genetic information for the benefit of patients with cancer. This review discusses the ethical, legal, and counseling issues surrounding disclosure of genetic information generated by NGS to patients with cancer and their relatives. We also provide a framework for returning these genetic results by proposing a design for a qualified disclosure policy.
Journal of Clinical Oncology 04/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The various phenotypes of hypospadias may result from disturbances of dissimilar embryonic processes in different time windows, suggesting aetiological heterogeneity; however, only a few studies have investigated the risk factors for the different hypospadias phenotypes. The study confirmed that genetic predisposition possibly plays a role in anterior and middle hypospadias, as shown by the large effect estimates for familial occurrence of these forms of hypospadias. By contrast, the posterior phenotype was more often associated with pregnancy-related factors, such as primiparity, preterm delivery, and being small for gestational age. New findings were that hormone-containing contraceptive use after conception increased the risk of middle and posterior hypospadias, while multiple pregnancies were associated with the posterior form in particular. OBJECTIVE: To identify specific risk factors for different phenotypes of hypospadias that may arise as a result of dissimilar embryonic processes in different time windows. PATIENTS AND METHODS: A total of 405 hypospadias cases and 627 male controls were included in a Dutch case-control study. Medical records of cases were reviewed to determine the anatomical location of the urethral opening, while demographic, lifestyle and pregnancy-related risk factor data were obtained from self-administered questionnaires. Multivariable and multinomial logistic regression analyses were used to calculate effect estimates for the group containing all cases of hypospadias and for the different hypospadias phenotypes. RESULTS: Cases were subdivided into anterior (glandular and coronal; 59%), middle (penile; 29%) and posterior (penoscrotal, scrotal and perineal; 12%) hypospadias. Being a twin/triplet, primiparity, preterm delivery, and being small for gestational age were associated with hypospadias, particularly in posterior cases. Family history of hypospadias increased the risk of hypospadias, an effect that seemed to be more predominant in anterior and middle forms. Maternal obesity seemed to increase the risk of hypospadias in general, and hormone-containing contraceptive use during pregnancy especially increased the risk of middle and posterior hypospadias. CONCLUSIONS: Our study provides some indications for aetiological heterogeneity of hypospadias, separating anterior and middle phenotypes from posterior hypospadias. Future research should continue to try to establish which specific risk factors and mechanisms may differ according to hypospadias phenotype.
[Show abstract][Hide abstract] ABSTRACT: Background
Focal segmental glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome. Hereditary FSGS is frequently caused by mutations in important structural podocyte proteins, including the slit diaphragm-associated transient receptor potential channel C6 (TRPC6).Methods
In five patients with biopsy-proven autosomal-dominant FSGS from five different Dutch families, all 13 exons of TRPC6 were sequenced. Upon identification of a novel TRPC6 sequence variant, the resultant amino acid change was introduced in the wild-type TRPC6 protein and functionally tested using patch-clamp analyses and cell-surface biotinylation experiments.ResultsNone of the previously described TRPC6 mutations were found in our cohort. In one family, we identified a novel c.524G>A sequence variant resulting in a p.Arg175Gln (R175Q) substitution in the TRPC6 protein. This sequence variant was absent in 449 control subjects and from public SNP databases. The mutation was located in the third ankyrin repeat domain (ANK3) in the cytoplasmic N-tail of TRPC6, important for protein-protein interaction and regulation of ion channel activity. Patch-clamp analyses of the mutant channel indeed showed an increased TRPC6 channel-mediated current. However, cell-surface expression of the mutant channel was not increased.Conclusions
We identified a novel TRPC6 p.Arg175Gln gain-of-function mutation that shows increased TRPC6-mediated current, which is not due to altered cell-surface expression. This is the first mutation identified in ANK3 of the TRPC6 N-tail and is most likely responsible for the late-onset autosomal dominant FSGS in this family.