Search Results (17)

Background/Objectives: Alport syndrome (AS) predominantly presents with X-linked inheritance worldwide. However, the epidemiological landscape remains poorly characterized, particularly among ethnic minority groups like the Roma minority in Slovakia. Our study aimed to investigate the inheritance patterns of AS in this region and determine whether a distinct pattern predominates. Methods: Selective genetic screening for pathogenic variants previously occurring in Slovakia was performed. Samples from patients with persistent (familial) hematuria ± hearing loss who had not yet undergone biopsy or genetic testing were analyzed by high-resolution melting analysis. The prevalence of AS per million (pm) population was calculated by adding information on patients with previously confirmed AS. Results: Twenty-five new cases of ARAS, one digenic form, and two cases of XLAS were identified by screening. In total, we collected information on 46 patients with genetically or bioptically confirmed AS in the region of eastern Slovakia, corresponding to a prevalence of 29 pm population. The c.1598G>A (p.Gly533Asp) pathogenic variant of the collagen type IV alpha 4 chain, which follows an autosomal recessive inheritance pattern, was the most prevalent variant that was exclusively confirmed in Roma patients (n = 35), suggesting a founder effect. Within the Roma community, the prevalence of ARAS (the most prevalent inheritance pattern) corresponds to 133 pm of the Roma population, based on midpoint population estimates. Conclusions: Our findings demonstrate a unique genetic profile of AS in the Roma population, characterized by a high prevalence of ARAS, with implications for genetic counseling and screening strategies. Full article

Chronic kidney disease (CKD) significantly affects canine health, but the precise cellular mechanisms of this condition remain elusive. In this study, we used single-cell RNA sequencing (scRNA-seq) to profile renal cellular gene expression in a canine model of X-linked hereditary nephropathy (XLHN). Dogs with this condition exhibit juvenile-onset CKD similar to that seen in human Alport syndrome. Post-mortem renal cortical tissues from an affected male dog and a heterozygous female dog were processed to obtain single-cell suspensions. In total, we recovered up to 13,190 cells and identified 11 cell types, including major kidney cells and immune cells. Differential gene expression analysis comparing the affected male and heterozygous female dogs identified cell-type specific pathways that differed in a subpopulation of proximal tubule cells. These pathways included the integrin signaling pathway and the pathway for inflammation mediated by chemokine and cytokine signaling. Additionally, using machine learning-empowered digital cytometry, we deconvolved bulk mRNA-seq data from a previous canine study, revealing changes in cell type proportions across CKD stages. These results underline the utility of single-cell methodologies and digital cytometry in veterinary nephrology. Full article

Pathogenic variants in type IV collagen genes (COL4A3, COL4A4, COL4A5) are classically associated with Alport syndrome (AS), a hereditary nephropathy primarily affecting the glomerular basement membrane (GBM). Recent findings, however, suggest a broader phenotypic spectrum that includes renal cyst formation, raising questions about overlapping mechanisms with other cystic kidney diseases. Clinically, renal cysts have been increasingly reported in patients with autosomal dominant and X-linked forms of Alport syndrome, particularly in association with glycine missense variants. The most recent studies focusing on the cystic phenotype in Alport syndrome provide growing support for the idea that variants in type IV collagen genes are associated with an increased likelihood of developing renal cysts, likely through mechanisms involving the structural integrity of renal basement membranes. In this review, we explore evidence from murine models and human studies indicating defects in collagen IV and discuss their contribution to cystogenesis. These observations underscore the need for broader genetic screening strategies and further investigation into the molecular mechanisms underlying this emerging phenotype. Full article

Background: Alport syndrome (AS) is one of the most common monogenic kidney disorders. Recent studies have highlighted the modifier effect of variants involving podocyte and non-collagenous extracellular matrix (ECM) proteins in AS. Methods: We report a case series of eight patients with genetically proven AS and simultaneous variants involving podocyte and non-collagenous ECM proteins. Our aim is to describe the influence of such variants on the phenotype of patients with AS. Results: We identified 10 different type IV collagen variants. Patients were diagnosed with autosomal dominant (3/8), autosomal recessive (2/8), digenic (2/8) and X-linked AS (1/8). There were eight different variants involving podocyte and non-collagenous ECM proteins. The genes involved were CRB2, LAMA5, LAMB2, NUP107, MYO1E and PLCE1. Four patients (LAMB2, LAMA5 and PLCE1 variants) presented with nephrotic syndrome or nephrotic range proteinuria. Two patients had hearing loss. Most patients (7/8) had a family history of kidney disease. Two patients (LAMB2 and LAMA5 variants) were diagnosed with focal segmental glomerulosclerosis. Two patients developed end-stage kidney disease (LAMA5, MYO1E and NUP107 variants). Conclusions: Although mutations of podocyte and ECM proteins do not have phenotypic expression in monoallelic form, the presence of such variants could explain the phenotypic variability of AS. Full article

Background: Alport syndrome (AS) is a clinically and genetically heterogeneous glomerulopathy resulting from pathogenic variants in COL4A3, COL4A4, and COL4A5. Genetic diagnosis is increasingly being conducted using next-generation sequencing (NGS). Methods: Within eight years, we examined a group of 247 Polish individuals and found in total 138 unrelated probands suspected with AS based on clinical course, laboratory findings, and/or family history, as well as the total of 109 family members. We applied a targeted NGS panel to identify the genetic spectrum of AS. Known and novel variants were revealed, and detailed evaluation was performed according to ACMG/AMP guidelines to classify them as pathogenic/likely pathogenic/VUS changes. Identified genotypes were compared with clinical manifestations: hematuria, proteinuria, chronic kidney disease, sensorineural hearing impairment, ocular abnormalities, and hypertension. Results: The molecular background was established in 109/138 probands. Overall, 79 different COL4A3-COL4A5 changes (56 known and 23 novel) were revealed. About 97% were SNVs, and only two COL4A5 CNVs were identified. In total, 11 recurrent COL4A3-COL4A5 variants were observed, including the most frequent COL4A5:p.Gly624Asp, accounting for 31% of X-linked AS. Conclusions: The use of NGS panel has shown considerable promise in the field of AS, increasing diagnostic rate to 79% and reducing time to diagnosis. The phenotype-driven gene panel, specific for genetic diseases in the pediatric population, is an affordable alternative to WGS and WES, offering comparable diagnostic efficacy and supporting its implementation as a first-line genetic test in rare diseases, including AS. Based on the obtained genotype–phenotype correlation, we assessed that NGS allows us to avoid invasive renal biopsy in AS diagnosis. It provides AS confirmation/exclusion, atypical AS identification, symptomatic/asymptomatic monoallelic COL4A3-COL4A5 carrier (especially COL4A5 females) determination, and inheritance pattern establishment. AS diagnosis confirmation enables clinical course prediction and is crucial for the early introduction of renoprotective treatment with renin–angiotensin–aldosterone system blockade, aimed at slowing the disease progression and estimating the risk in family members, which is important for genetic counselling. Full article

Background: Alport syndrome (AS) is a genetic disorder characterized by progressive renal disease, ocular abnormalities, and sensorineural hearing loss. However, the audiological profile of patients with AS remains elusive. Thus, this study aims to evaluate the natural history of auditory function in patients with AS. Methods: Exome or targeted sequencing for deafness genes was performed to confirm the pathogenic variants in patients with AS. Results: We identified fifteen individuals with AS who carried pathogenic variants of COL4A3, COL4A4, or COL4A5. Among fifteen, twelve (80%) showed hematuria, and six (40%) showed proteinuria. The patients exhibited bilateral sensorineural hearing loss, which was progressive and symmetric. The hearing thresholds increased according to age and plateaued at the level of 53 dB HL, indicating the hearing loss did not reach the severe-to-moderate level. The auditory dysfunction showed a distinct natural history depending on the inheritance pattern, but there was no remarkable difference between males and females among X-linked AS. Conclusions: Auditory dysfunction in AS is progressive up to the level of moderate hearing loss. Precise auditory rehabilitation for patients with AS is warranted depending on the inheritance pattern and genetic predisposition. Full article

Alport syndrome (AS) is a hereditary glomerulopathy due to pathogenic variants in COL4A3, COL4A4, and COL4A5. Treatment with Renin–Angiotensin–Aldosterone System (RAAS) inhibitors can delay progression to end stage renal disease (ESRD). From 2018 until today, we performed Whole Exome Sequencing (WES) in 19 patients with AS phenotype with or without positive family history. Fourteen of these patients were children. Genetic testing was extended to family members at risk. All patients received a genetic diagnosis of AS: five X-linked AS (XLAS) males, five X-linked AS (XLAS) females, six autosomal dominant AS (ADAS), and one autosomal recessive AS (ARAS). After cascade screening four XLAS males and eight XLAS females, six ADAS and three ARAS heterozygotes were added to our initial results. Fifteen patients were eligible to start treatment with RAAS inhibitors after their diagnosis. All XLAS female patients, ARAS heterozygotes, and ADAS have been advised to be followed up, so that therapeutic intervention can begin in the presence of microalbuminuria. Genetic diagnosis of AS ensures early therapeutic intervention and appropriate follow up to delay progression to chronic kidney disease, especially in thet pediatric population. Full article

Alport syndrome (AS) is a rare genetic disorder categorized by the progressive loss of kidney function, sensorineural hearing loss and eye abnormalities. It occurs due to mutations in three genes that encode for the alpha chains of type IV collagen. Globally, the disease is classified based on the pattern of inheritance into X-linked AS (XLAS), which is caused by pathogenic variants in COL4A5, representing 80% of AS. Autosomal recessive AS (ARAS), caused by mutations in either COL4A3 or COL4A4, represents 15% of AS. Autosomal dominant AS (ADAS) is rare and has been recorded in 5% of all cases due to mutations in COL4A3 or COL4A4. This review provides updated knowledge about AS including its clinical and genetic characteristics in addition to available therapies that only slow the progression of the disease. It also focuses on reported cases in Saudi Arabia and their prevalence. Moreover, we shed light on advances in genetic technologies like gene editing using CRISPR/Cas9 technology, the need for an early diagnosis of AS and managing the progression of the disease. Eventually, we provide a few recommendations for disease management, particularly in regions like Saudi Arabia where consanguineous marriages increase the risk. Full article

Background: Alport syndrome is a hereditary disorder caused by pathogenic variants in the COL4A gene, which can be inherited in an autosomal recessive, dominant, or X-linked pattern. In the Bukharian Jewish population, no founder pathogenic variant has been reported in COL4A4. Methods: The cohort included 38 patients from 22 Bukharian Jewish families with suspected Alport syndrome who were referred the nephrogenetics clinic between 2012 and 2022. The study collected demographic, clinical, and genetic data from electronic medical records, which were used to evaluate the molecular basis of the disease using Sanger sequencing, and next-generation sequencing. Results: Molecular diagnosis was confirmed in 20/38 patients, with each patient having at least one of the three disease-causing COL4A4 variants detected: c.338G<A (p.Gly113Asp), c.3022G>A (p.Gly1008Arg), and c.871-6T>C. In addition, two patients were obligate carriers. Overall, there were 17 heterozygotes, 2 compound heterozygotes, and 3 homozygotes. Each variant was detected in more than one unrelated family. All patients had hematuria with/without proteinuria at referral, and the youngest patient with proteinuria (age 5 years) was homozygous for the c.338G>A variant. End-stage renal disease was diagnosed in two patients at the age of 38 years, a compound heterozygote for c.338G>A and c.871-6T>C. Hearing deterioration was detected in three patients, the youngest aged 40 years, all of whom were heterozygous for c.338G>A. Conclusion: This study unveils three novel disease-causing variants, c.3022G>A, c.871-6T>C, and c.338G>A, in the COL4A4 gene that are recurrent among Jews of Bukharian ancestry, and cause Alport syndrome in both dominant and recessive autosomal inheritance patterns. Full article

Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, COL4A3/A4/A5. Pathogenic variants in COL4A5 are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the COL4A3 or the COL4A4 gene cause autosomal recessive AS. AS usually leads to progressive kidney failure before the age of 40-years when left untreated. People who inherit heterozygous COL4A3/A4 variants are at-risk of a slowly progressive form of the disease, starting with microscopic hematuria in early childhood, developing Alport spectrum nephropathy. Sometimes, they are diagnosed with benign familial hematuria, and sometimes with autosomal dominant AS. At diagnosis, they often show thin basement membrane nephropathy, reflecting the uniform thin glomerular basement membrane lesion, inherited as an autosomal dominant condition. On a long follow-up, most patients will retain normal or mildly affected kidney function, while a substantial proportion will develop chronic kidney disease (CKD), even kidney failure at an average age of 55-years. A question that remains unanswered is how to distinguish those patients with AS or with heterozygous COL4A3/A4 variants who will manifest a more aggressive kidney function decline, requiring prompt medical intervention. The hypothesis that a subgroup of patients coinherit additional genetic modifiers that exacerbate their clinical course has been investigated by several researchers. Here, we review all publications that describe the potential role of candidate genetic modifiers in patients and include a summary of studies in AS mouse models. Full article

Alport syndrome (AS) is a hereditary kidney disease caused by pathogenic variants in COL4A3 and COL4A4 genes with autosomal recessive or autosomal dominant transmission or in the COL4A5 gene with X-linked inheritance. Digenic inheritance was also described. Clinically it is associated with microscopic hematuria, followed by proteinuria and chronic renal insufficiency with end-stage renal disease in young adults. Nowadays, there is no curative treatment available. The inhibitors of RAS (renin-angiotensin system) since childhood slow the progression of the disease. Sodium-glucose cotransporter-2 inhibitors seem to be promising drugs from DAPA-CKD (dapagliflozin–chronic kidney disease) study, but only a limited number of patients with Alport syndrome was included. Endothelin type A receptor and angiotensin II type 1 receptor combined inhibitors, and lipid-lowering agents are used in ongoing studies in patients with AS and focal segmental glomerulosclerosis (FSGS). Hydroxychloroquine in AS is studied in a clinical trial in China. Molecular genetic diagnosis of AS is crucial not only for prognosis prediction but also for future therapeutic options. Different types of mutations will require various types of gene, RNA, or protein therapy to improve the function, the of final protein product. Full article

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis. Full article

Alport syndrome (AS) is a clinically and genetically heterogeneous disorder with a wide phenotypic spectrum, onset, and progression. X-linked AS (XLAS) and autosomal recessive AS (ARAS) are severe conditions, whereas the severity of autosomal dominant AS (ADAS) may vary from benign familial hematuria to progressive renal disease with extra-renal manifestations. In this study, we collated information from the literature and analyzed a cohort of 317 patients with ADAS carrying heterozygous disease-causing mutations in COL4A3/4 including four patients from two unrelated families who carried two novel variants in COL4A3. Regarding the age of onset of the disease, 80% of patients presented urinalysis alterations (microhematuria, hematuria, and/or proteinuria) before the age of 40 years. The cumulative probability of suffering adverse renal events was mainly observed between 30 and 70 years, without statistical differences between COL4A3 and COL4A4. We observed statistically significant differences between the sexes in the age of developing ESKD in cases affected by mutations in COL4A3/4 (p value = 0.0097), suggesting that males begin experiencing earlier deterioration of renal function than women. This study supports the importance of follow-up in young patients who harbor pathogenic mutations in COL4A3/4. We update the knowledge of ADAS, highlighting differences in the progression of the disease between males and females. Full article

Background: The goal of the treatment of Alport syndrome (AS) is to delay the progression of kidney damage. The current standard of care is the use of Renin Angiotensin Aldosterone System (RAAS) blockers: angiotensin-converting enzyme inhibition (ACEi), angiotensin receptor blockade, and, recently, spironolactone (SP). Aim of the study: the purpose of this retrospective study is to evaluate the efficacy (reduction of proteinuria and changes of glomerular function) and safety of a sequential introduction of RAAS blockers up to a triple RAAS blockade in pediatric proteinuric patients with AS. Methods: in this retrospective study (1995 to 2019), we evaluated proteinuria values in AS patients, during the 12 months following the beginning of a new RAAS blocker, up to a triple blockade. ACEi was always the first line of treatment; then ARB and SP were sequentially added if uPCR increased by 50% from the basal level in 2 consecutive samples during a 3-months observation period, or when uPCR ratio was >2 mg/mg. Results: 26 patients (mean age at treatment onset was 10.55 ± 5.02 years) were enrolled. All patients were on ACEi, 14/26 were started on a second drug (6/14 ARB, 8/14 SP) after a mean time of 2.2 ± 1.7 years, 7/26 were on triple RAAS blockade after a further period of 5.5 ± 2.3 years from the introduction of a second drug. Repeated Measure Anova analysis of log-transformed data shows that the reduction of uPCR values after Time 0 from the introduction of the first, second and third drug is highly significant in all three cases (p values = 0.0016, 0.003, and 0.014, respectively). No significant changes in eGFR were recorded in any group, apart from a 15-year-old boy with X-linked AS, who developed kidney failure. One patient developed mild hyperkaliemia, and one gynecomastia and symptomatic hypotension. No life-threatening events were recorded. Conclusions: double and triple RAAS blockade is an effective and safe strategy to reduce proteinuria in children with AS. Nevertheless, we suggest monitoring eGFR and Kaliemia during follow-up. Full article

Genetic studies of population isolates have great potential to provide a unique insight into genetic differentiation and phenotypic expressions. Galičnik village is a population isolate located in the northwest region of the Republic of North Macedonia, established around the 10th century. Alport syndrome-linked nephropathy with a complex inheritance pattern has been described historically among individuals in the village. In order to determine the genetic basis of the nephropathies and to characterize the genetic structure of the population, 23 samples were genotyped using a custom-made next generation sequencing panel and 111 samples using population genetic markers. We compared the newly obtained population data with fifteen European population data sets. NGS analysis revealed four different mutations in three different collagen genes in twelve individuals within the Galičnik population. The genetic isolation and small effective population size of Galičnik village have resulted in a high level of genomic homogeneity, with domination of R1a-M458 and R1b-U106* haplogroups. The study explains complex autosomal in cis digenic and X-linked inheritance patterns of nephropathy in the isolated population of Galičnik and describes the first case of Alport syndrome family with three different collagen gene mutations. Full article