1. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations
- Author
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Savige, Judith, Storey, Helen, Il Cheong, Hae, Gyung Kang, Hee, Park, Eujin, Hilbert, Pascale, Persikov, Anton, Torres-Fernandez, Carmen, Ars, Elisabet, Torra Balcells, Roser, Hertz, Jens Michael, Thomassen, Mads, Shagam, Lev, Wang, Dongmao, Wang, Yanyan, Flinter, Frances, Nagel, Mato, and Universitat Autònoma de Barcelona
- Subjects
0301 basic medicine ,Male ,030232 urology & nephrology ,lcsh:Medicine ,Otology ,Nephritis, Hereditary ,Deafness ,medicine.disease_cause ,urologic and male genital diseases ,Autoantigens ,Basement Membrane ,Database and Informatics Methods ,0302 clinical medicine ,Medicine and Health Sciences ,Missense mutation ,Renal Failure ,Age of Onset ,lcsh:Science ,Hearing Disorders ,Genetics ,Mutation ,Multidisciplinary ,Insertion Mutation ,medicine.diagnostic_test ,Nonsense Mutation ,Extracellular Matrix ,Deletion Mutation ,Nephrology ,Codon, Nonsense ,Female ,Cellular Structures and Organelles ,Research Article ,Adult ,Collagen Type IV ,Substitution Mutation ,Nonsense mutation ,Mutation, Missense ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,Young Adult ,medicine ,Journal Article ,Humans ,Alport syndrome ,Gene ,Genetic Association Studies ,Genetic testing ,Point mutation ,lcsh:R ,Biology and Life Sciences ,Cell Biology ,medicine.disease ,Alternative Splicing ,030104 developmental biology ,Biological Databases ,Otorhinolaryngology ,Mutation Databases ,lcsh:Q ,Age of onset ,Gene Deletion - Abstract
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 This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5,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 (pAla 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
- Published
- 2016