Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, ...COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS).
Retrospective cohort study.
82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected.
A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P=0.8), causative genes (P=0.6), or type of variant (P=0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was−1.46 (−1.66 to−1.26) mL/min/1.73m2 per year for the overall group, with no significant differences between ADAS genes (P=0.2).
The relatively small size of this series from a single country, potentially limiting generalizability.
Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.
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Abstract
Inherited kidney diseases (IKDs) are among the leading causes of early-onset chronic kidney disease (CKD) and are responsible for at least 10–15% of cases of kidney replacement therapy (KRT) ...in adults. Paediatric nephrologists are very aware of the high prevalence of IKDs among their patients, but this is not the case for adult nephrologists. Recent publications have demonstrated that monogenic diseases account for a significant percentage of adult cases of CKD. A substantial number of these patients have received a non-specific/incorrect diagnosis or a diagnosis of CKD of unknown aetiology, which precludes correct treatment, follow-up and genetic counselling. There are a number of reasons why genetic kidney diseases are difficult to diagnose in adulthood: (i) adult nephrologists, in general, are not knowledgeable about IKDs; (ii) existence of atypical phenotypes; (iii) genetic testing is not universally available; (iv) family history is not always available or may be negative; (v) lack of knowledge of various genotype–phenotype relationships and (vi) conflicting interpretation of the pathogenicity of many sequence variants. Registries can contribute to visualize the burden of IKDs by regularly grouping all IKDs in their annual reports, as is done for glomerulonephritis or interstitial diseases, rather than reporting only cystic disease and hiding other IKDs under labels such as ‘miscellaneous’ or ‘other’. Any effort to reduce the percentage of patients needing KRT with a diagnosis of ‘nephropathy of unknown etiology’ or an unspecific/incorrect diagnosis should be encouraged as a step towards precision nephrology. Genetic testing may be of value in this context but should not be used indiscriminately, but rather on the basis of a deep knowledge of IKDs.
Abstract
Background
Inherited kidney diseases are one of the leading causes of chronic kidney disease (CKD) that manifests before the age of 30 years. Precise clinical diagnosis of early-onset CKD is ...complicated due to the high phenotypic overlap, but genetic testing is a powerful diagnostic tool. We aimed to develop a genetic testing strategy to maximize the diagnostic yield for patients presenting with early-onset CKD and to determine the prevalence of the main causative genes.
Methods
We performed genetic testing of 460 patients with early-onset CKD of suspected monogenic cause using next-generation sequencing of a custom-designed kidney disease gene panel in addition to targeted screening for c.428dupC MUC1.
Results
We achieved a global diagnostic yield of 65% (300/460), which varied depending on the clinical diagnostic group: 77% in cystic kidney diseases, 76% in tubulopathies, 67% in autosomal dominant tubulointerstitial kidney disease, 61% in glomerulopathies and 38% in congenital anomalies of the kidney and urinary tract. Among the 300 genetically diagnosed patients, the clinical diagnosis was confirmed in 77%, a specific diagnosis within a clinical diagnostic group was identified in 15%, and 7% of cases were reclassified. Of the 64 causative genes identified in our cohort, 7 (COL4A3, COL4A4, COL4A5, HNF1B, PKD1, PKD2 and PKHD1) accounted for 66% (198/300) of the genetically diagnosed patients.
Conclusions
Two-thirds of patients with early-onset CKD in this cohort had a genetic cause. Just seven genes were responsible for the majority of diagnoses. Establishing a genetic diagnosis is crucial to define the precise aetiology of CKD, which allows accurate genetic counselling and improved patient management.
Molecular diagnosis of inherited kidney diseases remains a challenge due to their expanding phenotypic spectra as well as the constantly growing list of disease-causing genes. Here we develop a ...comprehensive approach for genetic diagnosis of inherited cystic and glomerular nephropathies. Targeted next generation sequencing of 140 genes causative of or associated with cystic or glomerular nephropathies was performed in 421 patients, a validation cohort of 116 patients with previously known mutations, and a diagnostic cohort of 207 patients with suspected inherited cystic disease and 98 patients with glomerular disease. In the validation cohort, a sensitivity of 99% was achieved. In the diagnostic cohort, causative mutations were found in 78% of patients with cystic disease and 62% of patients with glomerular disease, mostly familial cases, including copy number variants. Results depict the distribution of different cystic and glomerular inherited diseases showing the most likely diagnosis according to perinatal, pediatric and adult disease onset. Of all the genetically diagnosed patients, 15% were referred with an unspecified clinical diagnosis and in 2% genetic testing changed the clinical diagnosis. Therefore, in 17% of cases our genetic analysis was crucial to establish the correct diagnosis. Complex inheritance patterns in autosomal dominant polycystic kidney disease and Alport syndrome were suspected in seven and six patients, respectively. Thus, our kidney-disease gene panel is a comprehensive, noninvasive, and cost-effective tool for genetic diagnosis of cystic and glomerular inherited kidney diseases. This allows etiologic diagnosis in three-quarters of patients and is especially valuable in patients with unspecific or atypical phenotypes.
Alport syndrome (AS) is the most frequent inherited kidney disease after autosomal dominant polycystic kidney disease. It has three different patterns of inheritance-autosomal dominant, autosomal ...recessive and X-linked-which in part explains the wide spectrum of disease, ranging from isolated microhaematuria to end-stage renal disease early in life. The search for a treatment for AS is being pursued vigorously, not only because of the obvious unmet need but also because AS is a rare disease and any drug approved will have an orphan drug designation with its various benefits. Moreover, AS patients are quite young with very few comorbidities, which facilitates clinical trials. This review identifies the particularities of each pattern of inheritance but focuses mainly on new drugs or therapeutic targets for the disease. Most treatment-related investigations are directed not at the main abnormality in AS, namely collagen IV composition, but rather at the associated inflammation and fibrosis. Thus, AS may serve as a proof of concept for numerous drugs of potential value in many diseases that cause chronic kidney disease.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare underdiagnosed cause of end-stage renal disease (ESRD). ADTKD is caused by mutations in at least 4 different genes: MUC1, UMOD, ...HNF1B, and REN.
Retrospective cohort study.
56 families (131 affected individuals) with ADTKD referred from different Spanish hospitals. Clinical, laboratory, radiologic, and pathologic data were collected, and genetic testing for UMOD, MUC1, REN, and HNF1B was performed.
Hyperuricemia, ultrasound findings, renal histology, genetic mutations.
Age at ESRD, rate of decline in estimated glomerular filtration rate.
ADTKD was diagnosed in 25 families (45%), 9 carried UMOD pathogenic variants (41 affected members), and 16 carried the MUC1 pathogenic mutation c.(428)dupC (90 affected members). No pathogenic variants were identified in REN or HNF1B. Among the 77 individuals who developed ESRD, median age at onset of ESRD was 51 years for those with ADTKD-MUC1 versus 56 years (P=0.1) for those with ADTKD-UMOD. Individuals with the MUC1 duplication presented higher risk for developing ESRD (HR, 2.24; P=0.03). The slope of decline in estimated glomerular filtration rate showed no significant difference between groups (−3.0mL/min/1.73m2 per year in the ADTKD-UMOD group versus −3.9mL/min/1.73m2 per year in the ADTKD-MUC1 group; P=0.2). The prevalence of hyperuricemia was significantly higher in individuals with ADTKD-UMOD (87% vs 54%; P=0.006). Although gout occurred more frequently in this group, the difference was not statistically significant (24% vs 7%; P=0.07).
Relatively small Spanish cohort. MUC1 analysis limited to cytosine duplication.
The main genetic cause of ADTKD in our Spanish cohort is the MUC1 pathogenic mutation c.(428)dupC. Renal survival may be worse in individuals with the MUC1 mutation than in those with UMOD mutations. Clinical presentation does not permit distinguishing between these variants. However, hyperuricemia and gout are more frequent in individuals with ADTKD-UMOD.
Pain is the highest prioritized patient-reported outcome in people with autosomal dominant polycystic kidney disease (ADPKD) but it remains infrequently and inconsistently measured across countries, ...studies and trials. The study by El-Damanawi et al. integrated a network of ADPKD expert clinicians, pain specialists, researchers and patient representatives from the national UK PKD charity, with the aim of addressing the lack of validated ADPKD-specific pain assessment tools (APATs). The APAT designed by the authors included several pain measurement tools and was tested in ADPKD patients, although further validation through assessment in larger cohorts is needed. Establishing a standardized instrument for pain measurement will ensure that pain is measured and reported in a consistent way to inform decision-making and identify effective interventions aimed at managing pain and minimizing the impact pain has on patients with ADPKD. In this context, the APAT established by the authors is to be warmly welcomed.
Fabry disease or also called Anderson-Fabry disease (FD) is a rare disease caused by pathogenic variants in the GLA gene, located on the X chromosome. This gene is involved in the metabolism of ...glycosphingolipids and its pathogenic variants cause a deficit or absence of α-galactosidase A causing the deposition of globotriaosylceramide throughout the body. Females have a variable phenotypic expression and a better prognosis than males. This is due to the X chromosome inactivation phenomenon. We present a clinical case of Fabry disease in a female with predominantly renal involvement and demonstrate how the X chromosome inactivation phenomenon is tissue dependent, showing preferential inactivation of the mutated allele at the renal level.
La enfermedad de Fabry o también llamada de Anderson-Fabry (EF) es una enfermedad rara, causada por variantes patogénicas en el gen GLA, localizado en el cromosoma X. Este gen interviene en el metabolismo de los glucoesfingolípidos y variantes patogénicas en el mismo causan déficit o ausencia de la α-galactosidasa A ocasionando el depósito de globotriaosilceramida en todo el organismo. Las mujeres presentan una expresión fenotípica variable y de mejor pronóstico que los varones. Esto es debido al fenómeno de inactivación del cromosoma X. Presentamos un caso clínico de enfermedad de Fabry en una mujer con afectación predominantemente renal y demostramos cómo el fenómeno de la inactivación del cromosoma X es tejido dependiente, mostrando una inactivación preferencial del alelo mutado a nivel renal.
Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disorder characterized by early-onset nephrotic syndrome and microcephaly with brain anomalies. WDR73 pathogenic variants were described ...as the first genetic cause of GAMOS and, very recently, four novel causative genes, OSGEP, LAGE3, TP53RK, and TPRKB, have been identified.
We present the clinical and genetic characteristics of two unrelated infants with clinical suspicion of GAMOS who were born from consanguineous parents. Both patients showed a similar clinical presentation, with early-onset nephrotic syndrome, microcephaly, brain atrophy, developmental delay, axial hypotonia, and early fatality. We identified two novel likely disease-causing variants in the OSGEP gene. These two cases, in conjunction with the findings of a literature review, indicate that OSGEP pathogenic variants are associated with an earlier onset of nephrotic syndrome and shorter life expectancy than WDR73 pathogenic variants.
Our findings expand the spectrum of pathogenic variants in the OSGEP gene and, taken in conjunction with the results of the literature review, suggest that the OSGEP gene should be considered the main known monogenic cause of GAMOS. Early genetic diagnosis of GAMOS is of paramount importance for genetic counseling and family planning.
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