Genotype–phenotype correlations for COL4A3–COL4A5 variants resulting in Gly substitutions in Alport syndrome
Authors: Gibson Joel T. , Huang Mary , Shenelli Croos Dabrera Marina , Shukla Krushnam , Rothe Hansjörg , Hilbert Pascale , Deltas Constantinos , Storey Helen , Lipska-Ziętkiewicz Beata S. , Chan Melanie M. Y. , Sadeghi-Alavijeh Omid , Gale Daniel P. ,   Genomics England Research Consortium, Ambrose J. C. , Arumugam P. , Baple E. L. , Bleda M. , Boardman-Pretty F. , Boissiere J. M. , Boustred C. R. , Brittain H. , Caulfield M. J. , Chan G. C. , Craig C. E. H. , Daugherty L. C. , de Burca A. , Devereau A. , Elgar G. , Foulger R. E. , Fowler T. , Furió-Tarí P. , Giess A. , Hackett J. M. , Halai D. , Hamblin A. , Henderson S. , Holman J. E. , Hubbard T. J. P. , Ibáñez K. , Jackson R. , Jones L. J. , Kasperaviciute D. , Kayikci M. , Kousathanas A. , Lahnstein L. , Lawson K. , Leigh S. E. A. , Leong I. U. S. , Lopez F. J. , Maleady-Crowe F. , Mason J. , McDonagh E. M. , Moutsianas L. , Mueller M. , Murugaesu N. , Need A. C. , Odhams C. A. , Orioli A. , Patch C. , Perez-Gil D. , Pereira M. B. , Polychronopoulos D. , Pullinger J. , Rahim T. , Rendon A. , Riesgo-Ferreiro P. , Rogers T. , Ryten M. , Savage K. , Sawant K. , Scott R. H. , Siddiq A. , Sieghart A. , Smedley D. , Smith K. R. , Smith S. C. , Sosinsky A. , Spooner W. , Stevens H. E. , Stuckey A. , Sultana R. , Tanguy M. , Thomas E. R. A. , Thompson S. R. , Tregidgo C. , Tucci A. , Walsh E. , Watters S. A. , Welland M. J. , Williams E. , Witkowska K. , Wood S. M. , Zarowiecki M. , Cerkauskaite Agne , Savige Judy 
Published: February 2022

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.