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Clinical Journal of the American... Jan 2022Genetic testing for pathogenic variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney...
Genetic testing for pathogenic variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic or is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that or heterozygotes do not act as kidney donors. Testing for variants in the genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.
Topics: Autoantigens; Collagen Type IV; Genetic Testing; Humans; Nephritis, Hereditary; Practice Guidelines as Topic
PubMed: 34930753
DOI: 10.2215/CJN.04230321 -
Clinical Journal of the American... Nov 2022Digenic Alport syndrome refers to the inheritance of pathogenic variants in plus or or in plus Where digenic Alport syndrome includes a pathogenic variant, the... (Review)
Review
Digenic Alport syndrome refers to the inheritance of pathogenic variants in plus or or in plus Where digenic Alport syndrome includes a pathogenic variant, the consequences depend on the sex of the affected individual, variant "severity," and the nature of the or change. A man with a pathogenic variant has all his collagen IV 345-heterotrimers affected, and an additional or variant may not worsen disease. A woman with a pathogenic variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further or variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic and variants, 75% of the heterotrimers are affected. The and genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome () or recessive when they affect different chromosomes (). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if and variants are known to be inherited on the same or different chromosomes.
Topics: Humans; Male; Female; Nephritis, Hereditary; Pedigree; Autoantigens; Collagen Type IV; Proteinuria; Mutation
PubMed: 35675912
DOI: 10.2215/CJN.03120322 -
Clinical and Experimental Nephrology Feb 2019Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three... (Review)
Review
Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4. Diagnosis is conventionally made pathologically, but recent advances in comprehensive genetic analysis have enabled genetic testing to be performed for the diagnosis of AS as first-line diagnosis. Because of these advances, substantial information about the genetics of AS has been obtained and the genetic background of this disease has been revealed, including genotype-phenotype correlations and mechanisms of onset in some male XLAS cases that lead to milder phenotypes of late-onset end-stage renal disease (ESRD). There is currently no radical therapy for AS and treatment is only performed to delay progression to ESRD using nephron-protective drugs. Angiotensin-converting enzyme inhibitors can remarkably delay the development of ESRD. Recently, some new drugs for this disease have entered clinical trials or been developed in laboratories. In this article, we review the diagnostic strategy, genotype-phenotype correlation, mechanisms of onset of milder phenotypes, and treatment of AS, among others.
Topics: Adult; Animals; Autoantigens; Collagen Type IV; Female; Genetic Association Studies; Genetic Predisposition to Disease; Heredity; Humans; Kidney; Male; Mutation; Nephritis, Hereditary; Phenotype; Prognosis; Risk Factors; Young Adult
PubMed: 30128941
DOI: 10.1007/s10157-018-1629-4 -
Clinical Journal of the American... Dec 2022Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We randomly assigned patients with Alport syndrome, ages 12-70 years and eGFR 30-90 ml/min per 1.73 m, to bardoxolone methyl (=77) or placebo (=80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight.
RESULTS
Patients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4; <0.001] and 7.4 [95% confidence interval, 3.1 to 11.7; =0.0008] ml/min per 1.73 m, respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1; <0.001) and 4.4 (95% confidence interval, 0.7 to 8.1; =0.02) ml/min per 1.73 m at 52 and 104 weeks, respectively. In a analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 [95% confidence interval, -1.9 to 4.9] ml/min per 1.73 m). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure.
CONCLUSIONS
In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185.
Topics: Adult; Adolescent; Humans; Child; Young Adult; Middle Aged; Aged; Nephritis, Hereditary; Diabetes Mellitus, Type 2; Oleanolic Acid; Glomerular Filtration Rate; Double-Blind Method
PubMed: 36411058
DOI: 10.2215/CJN.02400222 -
Pediatric Nephrology (Berlin, Germany) Jul 2019Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In... (Review)
Review
Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.
Topics: Autoantigens; Collagen Type IV; Consensus; DNA Mutational Analysis; Genetic Testing; Genotype; High-Throughput Nucleotide Sequencing; Humans; Mutation; Nephritis, Hereditary; Phenotype; Practice Guidelines as Topic
PubMed: 29987460
DOI: 10.1007/s00467-018-3985-4 -
American Journal of Kidney Diseases :... Oct 2021Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic...
RATIONALE & OBJECTIVE
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).
STUDY DESIGN
Retrospective cohort study.
SETTING & PARTICIPANTS
82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected.
OBSERVATIONS
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/1.73m per year for the overall group, with no significant differences between ADAS genes (P=0.2).
LIMITATIONS
The relatively small size of this series from a single country, potentially limiting generalizability.
CONCLUSIONS
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.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoantigens; Cohort Studies; Collagen Type IV; Female; Genetic Testing; Genetic Variation; Humans; Male; Middle Aged; Nephritis, Hereditary; Renal Insufficiency; Retrospective Studies; Young Adult
PubMed: 33838161
DOI: 10.1053/j.ajkd.2021.02.326 -
Clinical Journal of the American... Aug 2016Alport syndrome comprises a group of inherited heterogeneous disorders involving CKD, hearing loss, and ocular abnormalities. Autosomal dominant Alport syndrome caused...
BACKGROUND AND OBJECTIVES
Alport syndrome comprises a group of inherited heterogeneous disorders involving CKD, hearing loss, and ocular abnormalities. Autosomal dominant Alport syndrome caused by heterozygous mutations in collagen 4A3 and/or collagen 4A4 accounts for <5% of patients. However, the clinical, genetic, and pathologic backgrounds of patients with autosomal dominant Alport syndrome remain unclear.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We conducted a retrospective analysis of 25 patients with genetically proven autosomal dominant Alport syndrome and their family members (a total of 72 patients) from 16 unrelated families. Patients with suspected Alport syndrome after pathologic examination who were referred from anywhere in Japan for genetic analysis from 2006 to 2015 were included in this study. Clinical, laboratory, and pathologic data were collected from medical records at the point of registration for genetic diagnosis. Genetic analysis was performed by targeted resequencing of 27 podocyte-related genes, including Alport-related collagen genes, to make a diagnosis of autosomal dominant Alport syndrome and identify modifier genes or double mutations. Clinical data were obtained from medical records.
RESULTS
The median renal survival time was 70 years, and the median age at first detection of proteinuria was 17 years old. There was one patient with hearing loss and one patient with ocular lesion. Among 16 patients who underwent kidney biopsy, three showed FSGS, and seven showed thinning without lamellation of the glomerular basement membrane. Five of 13 detected mutations were reported to be causative mutations for autosomal recessive Alport syndrome in previous studies. Two families possessed double mutations in both collagen 4A3 and collagen 4A4, but no modifier genes were detected among the other podocyte-related genes.
CONCLUSIONS
The renal phenotype of autosomal dominant Alport syndrome was much milder than that of autosomal recessive Alport syndrome or X-linked Alport syndrome in men. It may, thus, be difficult to make an accurate diagnosis of autosomal dominant Alport syndrome on the basis of clinical or pathologic findings. No modifier genes were identified among the known podocyte-related genes.
Topics: Adolescent; Adult; Age of Onset; Aged; Aged, 80 and over; Autoantigens; Biopsy; Child; Child, Preschool; Collagen Type IV; DNA Mutational Analysis; Female; Genetic Testing; Haplotypes; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Mutation, Missense; Nephritis, Hereditary; Pedigree; Phenotype; Proteinuria; Retrospective Studies; Young Adult
PubMed: 27281700
DOI: 10.2215/CJN.01000116 -
Kidney International May 2018Mutations in the genes COL4A3, COL4A4, and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous...
Mutations in the genes COL4A3, COL4A4, and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous constituent of the mature mammalian glomerular basement membrane. These mutations are associated with a spectrum of nephropathy, from microscopic hematuria to progressive renal disease leading to ESRD, and with extrarenal manifestations such as sensorineural deafness and ocular anomalies. The existing nomenclature for these conditions is confusing and can delay institution of appropriate nephroprotective therapy. Herein we propose a new classification of genetic disorders of the collagen IV α345 molecule with the goal of improving renal outcomes through regular monitoring and early treatment.
Topics: Autoantigens; Collagen Type IV; Consensus; DNA Mutational Analysis; Genetic Markers; Genetic Predisposition to Disease; Humans; Mutation; Nephritis, Hereditary; Phenotype; Predictive Value of Tests; Prognosis; Terminology as Topic
PubMed: 29551517
DOI: 10.1016/j.kint.2017.12.018 -
Journal of the American Society of... Dec 2013Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport...
Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport syndrome is suspected in consanguineous families and when female patients develop renal failure. Fifteen percent of patients with Alport syndrome have autosomal recessive inheritance caused by two pathogenic mutations in either COL4A3 or COL4A4. Here, we describe the mutations and clinical features in 40 individuals including 9 children and 21 female individuals (53%) with autosomal recessive inheritance indicated by the detection of two mutations. The median age was 31 years (range, 6-54 years). The median age at end stage renal failure was 22.5 years (range, 10-38 years), but renal function was normal in nine adults (29%). Hearing loss and ocular abnormalities were common (23 of 35 patients [66%] and 10 of 18 patients [56%], respectively). Twenty mutation pairs (50%) affected COL4A3 and 20 pairs affected COL4A4. Of the 68 variants identified, 39 were novel, 12 were homozygous changes, and 9 were present in multiple individuals, including c.2906C>G (p.(Ser969*)) in COL4A4, which was found in 23% of the patients. Thirty-six variants (53%) resulted directly or indirectly in a stop codon, and all 17 individuals with early onset renal failure had at least one such mutation, whereas these mutations were less common in patients with normal renal function or late-onset renal failure. In conclusion, patient phenotypes may vary depending on the underlying mutations, and genetic testing should be considered for the routine diagnosis of autosomal recessive Alport syndrome.
Topics: Adolescent; Adult; Autoantigens; Child; Collagen Type IV; Eye Diseases; Female; Genes, Recessive; Genetic Testing; Hearing Loss, Sensorineural; Humans; Male; Middle Aged; Mutation; Nephritis, Hereditary; Phenotype; Young Adult
PubMed: 24052634
DOI: 10.1681/ASN.2012100985 -
Improving mutation screening in familial hematuric nephropathies through next generation sequencing.Journal of the American Society of... Dec 2014Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5...
Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.
Topics: Adolescent; Adult; Autoantigens; Child; Child, Preschool; Cohort Studies; Collagen Type IV; DNA Mutational Analysis; Family Health; Female; Genetic Counseling; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Mutation; Nephritis, Hereditary; Phenotype; Polymorphism, Single Nucleotide; Young Adult
PubMed: 24854265
DOI: 10.1681/ASN.2013080912