title: X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.
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 This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5,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 (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.
authors.affiliation: The University of Melbourne, Melbourne Health and Northern Health, Melbourne, Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Savige
authors.affiliation: Molecular Genetics Laboratory, Guy's and St Thomas' Hospital, London, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Storey
authors.affiliation: Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea.
authors.forename: Hae
authors.initials: H
authors.lastname: Il Cheong
authors.affiliation: Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea.
authors.forename: Hee
authors.initials: H
authors.lastname: Gyung Kang
authors.affiliation: Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea.
authors.forename: Eujin
authors.initials: E
authors.lastname: Park
authors.affiliation: Institut de Pathologie et Genetique, Department of Molecular Biology, Gosselles, Belgium.
authors.forename: Pascale
authors.initials: P
authors.lastname: Hilbert
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Anton
authors.initials: A
authors.lastname: Persikov
authors.affiliation: Molecular Genetics Centre GENETAQ, Malaga, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Torres-Fernandez
authors.affiliation: Molecular Biology Laboratory and Department of Nephrology, REDINREN, Fundacio Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ars
authors.affiliation: Molecular Biology Laboratory and Department of Nephrology, REDINREN, Fundacio Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Torra
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Jens Michael
authors.initials: JM
authors.lastname: Hertz
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Thomassen
authors.affiliation: Institute of Pediatrics, Pirogov Russian Medical University, Moscow, Russia.
authors.forename: Lev
authors.initials: L
authors.lastname: Shagam
authors.affiliation: The University of Melbourne, Melbourne Health and Northern Health, Melbourne, Australia.
authors.forename: Dongmao
authors.initials: D
authors.lastname: Wang
authors.affiliation: The University of Melbourne, Melbourne Health and Northern Health, Melbourne, Australia.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Genetics, Guy's and St Thomas' Hospital, London, United Kingdom.
authors.forename: Frances
authors.initials: F
authors.lastname: Flinter
authors.affiliation: Centre for Nephrology and Metabolic Medicine, Weisswasser D-02943, Germany.
authors.forename: Mato
authors.initials: M
authors.lastname: Nagel
mesh_terms: D000328:Adult; D017668:Age of Onset; D017398:Alternative Splicing / Q000235:genetics; D001324:Autoantigens / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D024141:Collagen Type IV / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D009394:Nephritis, Hereditary / Q000235:genetics / Q000473:pathology*; D055815:Young Adult
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; C478159:COL4A5 protein, human; D018389:Codon, Nonsense; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain