ArticleScientific reports2022
Genotype-phenotype correlations for COL4A3-COL4A5 variants resulting in Gly substitutions in Alport syndrome.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- Diagnosis, management and treatment of the Alport syndrome - 2024 guideline on behalf of ERKNet, ERA and ESPN.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2025Guideline
- 'Missing' disease-causing variants in Alport syndrome.Nature reviews. Nephrology · 2026Review
- Functional validation of spliceogenic COL4A3 and COL4A4 variants by minigene assays refines molecular diagnosis of Alport syndrome.Human genomics · 2026Article
- Phenotype of autosomal dominant Alport syndrome with a likely pathogenic heterozygous variant in the COL4A3 gene (Gly366Arg) and incidental teratozoospermia: A case report.Anales del sistema sanitario de Navarra · 2026Article
- Identification of end-stage renal disease-associated loci in X chromosome: an X chromosome-wide association study.MedScience · 2026Article
- Sequential sequencing reveals the architecture and complexity of genomic variants in patients with Alport syndrome.Nature communications · 2026Article
- The Importance of Molecular Testing in the Diagnosis of Genetic Syndromes with Chronic Kidney Disease: Genotype-Phenotype Correlations.International journal of molecular sciences · 2026Article
- Genetic heterogeneity correlated with phenotypic variability in 6 Chinese families with Alport syndrome.Frontiers in genetics · 2026Article
- Age at disease onset and risk of chronic kidney disease in patients with heterozygous disease-causing variants inClinical kidney journal · 2025Article
- Genotype-First Analysis in an Unselected Health System-Based Population and Phenotypic Severity of COL4A5 Variants.Journal of the American Society of Nephrology : JASN · 2025Article
- Genotype-Based Molecular Mechanisms in Alport Syndrome.Journal of the American Society of Nephrology : JASN · 2025Review
- Pathogenic variants in the Alport genes are prevalent in the Singapore multiethnic population with highest frequency in the Chinese.Scientific reports · 2025Article
- Detection of Alport gene variants in children and young people with persistent haematuria.Pediatric nephrology (Berlin, Germany) · 2025Article
- Candidate Genetic Modifiers in Alport Syndrome: A Case Series.Life (Basel, Switzerland) · 2025Article
- Article
- A guide to gene-disease relationships in nephrology.Nature reviews. Nephrology · 2025Review
- Anticodon-edited tRNA enables translational readthrough of COL4A5 premature termination codons.PloS one · 2025Article
- Identification of a novel intronic variant in COL4A2 gene associated with fetal severe cerebral encephalomalacia and subdural hemorrhage.BMC medical genomics · 2024Article
- Genotype-first analysis in an unselected health system-based population reveals variable phenotypic severity ofmedRxiv : the preprint server for health sciences · 2024Article
- Article
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15 authors at 12 institutions in 6 countries.
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Abstract
Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3-COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p < 0.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome.
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