Expert consensus guidelines for the genetic diagnosis of Alport syndrome

被引:114
作者
Savige, Judy [1 ]
Ariani, Francesca [2 ]
Mari, Francesca [2 ]
Bruttini, Mirella [2 ]
Renieri, Alessandra [2 ]
Gross, Oliver [3 ]
Deltas, Constantinos [4 ]
Flinter, Frances [5 ]
Ding, Jie [6 ]
Gale, Daniel P. [7 ]
Nagel, Mato [8 ]
Yau, Michael [9 ]
Shagam, Lev [10 ]
Torra, Roser [11 ]
Ars, Elisabet [12 ]
Hoefele, Julia [13 ]
Garosi, Guido [14 ]
Storey, Helen [9 ]
机构
[1] Univ Melbourne, Melbourne & Northern Hlth, Dept Med, Parkville, Vic 3050, Australia
[2] Univ Siena, Med Genet, Siena, Italy
[3] Univ Gottingen, Clin Nephrol & Rheumatol, Gottingen, Germany
[4] Univ Cyprus, Mol Med Res Ctr, Nicosia, Cyprus
[5] Guys & St Thomas NHS Fdn Trust, Dept Clin Genet, London, England
[6] Peking Univ, Hosp 1, Beijing, Peoples R China
[7] UCL, Royal Free Hosp, Ctr Nephrol, London, England
[8] Ctr Nephrol & Metab Disorders, Weisswasser, Germany
[9] Viapath, Guys Hosp, Genet, London, England
[10] Pirogov Russian Med Univ, Inst Pediat, Moscow, Russia
[11] Univ Autonoma Barcelona, Inst Invest Carlos III, Fundacio Puigvert, Inherited Kidney Disorders,Nephrol Dept, Barcelona, Spain
[12] Univ Autonoma Barcelona, Inst Invest Carlos III, Fundacio Puigvert, Mol Biol Lab, Barcelona, Spain
[13] Tech Univ Munich, Inst Human Genet, Munich, Germany
[14] Azienda Osped Univ Senese, Nephrol Dialysis & Transplantat, Siena, Italy
关键词
Alport syndrome; Collagen IV genes; Next generation sequencing; Pathogenic variants; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GENOTYPE-PHENOTYPE CORRELATIONS; BASEMENT-MEMBRANE NEPHROPATHY; SOMATIC MOSAICISM; COLLAGEN-IV; COL4A5; GENE; COL4A3/COL4A4; MUTATIONS; UNCLASSIFIED VARIANTS; DIGENIC INHERITANCE; SEQUENCE VARIANTS;
D O I
10.1007/s00467-018-3985-4
中图分类号
R72 [儿科学];
学科分类号
100202 ;
摘要
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.
引用
收藏
页码:1175 / 1189
页数:15
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