1. Precise variant interpretation, phenotype ascertainment, and genotype–phenotype correlation of children in the<scp>EARLY PRO‐TECT</scp>Alport trial
- Author
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Early Pro-Tect Alport Investigators, Tim Friede, Michaela Gessner, Peter F. Hoyer, Henry Fehrenbach, Rasmus Ehren, Jutta Gellermann, Ulrike John, M Pohl, Baerbel Lange-Sperandio, Matthias Galiano, Carsten Bergmann, Bernd Hoppe, Lars Pape, Burkhard Tönshoff, Oliver Gross, Hagen Staude, Matthias Kettwig, Julia Hoefele, Kay Latta, Martin Konrad, Jan Boeckhaus, and Korbinian M. Riedhammer
- Subjects
Collagen Type IV ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Medizin ,Nephritis, Hereditary ,macromolecular substances ,030105 genetics & heredity ,Kidney ,Early initiation ,Genotype phenotype ,Correlation ,03 medical and health sciences ,Genes, X-Linked ,Internal medicine ,Genetics ,Humans ,Medicine ,ddc:610 ,Genetic Testing ,Renal Insufficiency ,Alport syndrome ,Child ,Genetic Association Studies ,Genetics (clinical) ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Infant ,medicine.disease ,Phenotype ,ddc ,3. Good health ,Early Diagnosis ,030104 developmental biology ,Sample size determination ,Child, Preschool ,Cohort ,Female ,business - Abstract
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.
- Published
- 2020