Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial.
Alport syndrome
COL4A3
COL4A4
COL4A5
hereditary kidney disease
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
04
08
2020
revised:
18
09
2020
accepted:
05
10
2020
pubmed:
12
10
2020
medline:
1
10
2021
entrez:
11
10
2020
Statut:
ppublish
Résumé
Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.
Substances chimiques
COL4A5 protein, human
0
Collagen Type IV
0
Banques de données
ClinicalTrials.gov
['NCT01485978']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
143-156Informations de copyright
© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
Références
Hertz JM, Thomassen M, Storey H, Flinter F. Clinical utility gene card for: alport syndrome - update 2014. Eur J Hum Genet. 2015;23(9):1269.
Kruegel J, Rubel D, Gross O. Alport syndrome-insights from basic and clinical research. Nat Rev Nephrol. 2013;9(3):170-178.
Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med. 2003;348(25):2543-2556.
Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M. Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. Nephrol Dial Transplant. 2002;17(7):1218-1227.
Moriniere V, Dahan K, Hilbert P, et al. Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol. 2014;25(12):2740-2751.
Bekheirnia MR, Reed B, Gregory MC, et al. Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol. 2010;21(5):876-883.
Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol. 2000;11(4):649-657.
Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport syndrome concerted action" study. J Am Soc Nephrol. 2003;14(10):2603-2610.
Savige J, Colville D, Rheault M, et al. Alport syndrome in women and girls. Clin J Am Soc Nephrol. 2016;11(9):1713-1720.
Yamamura T, Nozu K, Fu XJ, et al. Natural history and genotype-phenotype correlation in female X-linked Alport syndrome. Kidney Int Rep. 2017;2(5):850-855.
Mencarelli MA, Heidet L, Storey H, et al. Evidence of digenic inheritance in Alport syndrome. J Med Genet. 2015;52(3):163-174.
Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241.
Fallerini C, Dosa L, Tita R, et al. Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases. Clin Genet. 2014;86(3):252-257.
Voskarides K, Damianou L, Neocleous V, et al. COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy. J Am Soc Nephrol. 2007;18(11):3004-3016.
Kashtan CE. Alport syndromes: phenotypic heterogeneity of progressive hereditary nephritis. Pediatr Nephrol. 2000;14(6):502-512.
Barker DF, Pruchno CJ, Jiang X, et al. A mutation causing Alport syndrome with tardive hearing loss is common in the western United States. Am J Hum Genet. 1996;58(6):1157-1165.
Govan JA. Ocular manifestations of Alport's syndrome: a hereditary disorder of basement membranes? Br J Ophthalmol. 1983;67(8):493-503.
Nielsen CE. Lenticonus anterior and Alport's syndrome. Acta Ophthalmol. 1978;56(4):518-530.
Haas M. Alport syndrome and thin glomerular basement membrane nephropathy: a practical approach to diagnosis. Arch Pathol Lab Med. 2009;133(2):224-232.
Savige J, Storey H, Il Cheong H, et al. X-linked and autosomal recessive Alport syndrome: pathogenic variant features and further genotype-phenotype correlations. PloS One. 2016;11(9):e0161802.
Gross O, Licht C, Anders HJ, et al. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012;81(5):494-501.
Gross O, Friede T, Hilgers R, et al. Safety and efficacy of the ACE-inhibitor Ramipril in Alport syndrome: the double-blind, randomized, placebo-controlled, multicenter phase III EARLY PRO-TECT Alport trial in pediatric patients. ISRN Pediatr. 2012;2012:436046.
Gross O, Tonshoff B, Weber LT, et al. A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome. Kidney Int. 2020;97(6):1275-1286.
Kremer LS, Bader DM, Mertes C, et al. Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat Commun. 2017;8:15824.
Griffin HR, Pyle A, Blakely EL, et al. Accurate mitochondrial DNA sequencing using off-target reads provides a single test to identify pathogenic point mutations. Genet Med. 2014;16(12):962-971.
Plagnol V, Curtis J, Epstein M, et al. A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics. 2012;28(21):2747-2754.
Abou Tayoun AN, Pesaran T, DiStefano MT, et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum Mutat. 2018;39(11):1517-1524.
Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST. Working Group of the American College of medical genetics laboratory quality assurance C. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13(7):680-685.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
Ellard S, Baple EL, Berry I, et al. ACGS Best Practice Guidelines for Variant Classification 2019. https://www.acgs.uk.com/media/11285/uk-practice-guidelines-for-variant-classification-2019-v1-0-3.pdf. 2019.
Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the clinical genome resource (ClinGen). Genet Med. 2020;22(2):245-257.
Ryu M, Kulkarni OP, Radomska E, Miosge N, Gross O, Anders HJ. Bacterial CpG-DNA accelerates Alport glomerulosclerosis by inducing an M1 macrophage phenotype and tumor necrosis factor-alpha-mediated podocyte loss. Kidney Int. 2011;79(2):189-198.
Pierides A, Voskarides K, Kkolou M, Hadjigavriel M. Deltas C. X-linked, COL4A5 hypomorphic Alport mutations such as G624D and P628L may only exhibit thin basement membrane nephropathy with microhematuria and late onset kidney failure. Hippokratia. 2013;17(3):207-213.
Macheroux EP, Braunisch MC, Pucci Pegler S, et al. The Hypomorphic variant p.(Gly624Asp) in COL4A5 as a possible cause for an unexpected severe phenotype in a family with X-linked Alport syndrome. Front Pediatr. 2019;7:485.