A female with X-linked Alport syndrome and compound heterozygous COL4A5 mutations

Mohammad, Mardhiah; Nanra, R. S.; Colville, Deb; Trevillian, Paul; Wang, Yanyan; Storey, Helen; Flinter, Frances; Savige, Judy

doi:10.1007/s00467-013-2682-6

Cited by 14 publications

(7 citation statements)

References 15 publications

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“…There are occasional reports of individuals with two COL4A5 mutations [ 22 , 23 ], and others with autosomal recessive Alport syndrome and mutations in both COL4A3 and COL4A4 with a later age at onset of renal failure [ 15 , 24 , 25 ].…”

Section: Resultsmentioning

confidence: 99%

X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations

et al. 2016

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Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher’s exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10−41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure occurred sooner with two non-missense variants (p = 0.08, and p = 0.01 respectively). Thus DNA variant characteristics that predict age at renal failure appeared to be the same for all three Alport genes. Founder mutations (with the pathogenic variant in at least 5 apparently- unrelated individuals) were not necessarily associated with a milder phenotype. This study illustrates the benefits when routine diagnostic laboratories share and analyse their data.

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Section: Resultsmentioning

confidence: 99%

X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations

et al. 2016

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“…Among 578 missense variants, 14 (2.4%) pathogenic variants caused by single-base substitutions at the last nucleotide positions in exons were included in this study (Figure 1 and Table 1). 5, [24][25][26][27][28][29][30][31][32][33][34][35][36] In addition, 6 novel variants in our cohort were included. Finally, 20 variants were included in this study.…”

Section: Analyzed Variantsmentioning

confidence: 99%

Last Nucleotide Substitutions of COL4A5 Exons Cause Aberrant Splicing

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et al. 2022

Kidney International Reports

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“…There are increasing reports of biallelic and digenic variants in Alport syndrome. There are also examples of variants in COL4A3 and COL4A4 in trans [17,18], and a single report of a woman with two pathogenic COL4A5 variants in trans [70]. In trans mutations are confirmed when the parents are each demonstrated to have one variant.…”

Section: Biallelic and Digenic Mutations Affect The Clinical Phenotypmentioning

confidence: 99%

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

et al. 2018

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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.

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A female with X-linked Alport syndrome and compound heterozygous COL4A5 mutations

Cited by 14 publications

References 15 publications

X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations

X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations

Last Nucleotide Substitutions of COL4A5 Exons Cause Aberrant Splicing

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

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