ESPN 54th Annual Meeting

ESPN 2022


 
Genotype-phenotype correlation in a cohort of individuals with disease-causing variants in COL4A3/COL4A4 associated with type-IV-collagen-related nephropathy (Alport syndrome and thin basement membrane nephropathy)
SIMMENDINGER HANNES 1 RIEDHAMMER KORBINIAN MARIA 1 TASIC VELIBOR 3 PUTNIK JOVANA 4 ABAZI-EMINI NORA 3 STAJIC NATASA 4 WEIDENBUSCH MARC 5 PATZER LUDWIG 6 LUNGU ADRIAN 7 MILOSEVSKI-LOMIC GORDANA 4 BRAUNISCH MATTHIAS 2 GÜNTHNER ROMAN 2 COMIC JASMINA 1 HOEFELE JULIA 1

1- INSTITUTE OF HUMAN GENETICS, KLINIKUM RECHTS DER ISAR, TECHNICAL UNIVERSITY OF MUNICH, SCHOOL OF MEDICINE, MUNICH, GERMANY
2- DEPARTMENT OF NEPHROLOGY, KLINIKUM RECHTS DER ISAR, TECHNICAL UNIVERSITY OF MUNICH, SCHOOL OF MEDICINE, MUNICH, GERMANY
3- UNIVERSITY CHILDREN’S HOSPITAL, MEDICAL FACULTY OF SKOPJE, MACEDONIA
4- INSTITUTE FOR MOTHER AND CHILD HEALTH CARE OF SERBIA "DR VUKAN ČUPIĆ", DEPARTMENT OF NEPHROLOGY, UNIVERSITY OF BELGRADE, FACULTY OF MEDICINE, BELGRADE, SERBIA
5- NEPHROLOGISCHES ZENTRUM, MEDIZINISCHE KLINIK UND POLIKLINIK IV, KLINIKUM DER UNIVERSITäT MÜNCHEN, LUDWIG-MAXIMILIANS UNIVERSITY, MUNICH, GERMANY
6- CHILDRENS HOSPITAL ST. ELISABETH AND ST. BARBARA, HALLE/SAALE, GERMANY
7- FUNDENI CLINICAL INSTITUTE, PEDIATRIC NEPHROLOGY DEPARTMENT, BUCHAREST, ROMANIA
 
Introduction:

Type-IV-collagen-related nephropathies comprising Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) show a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 are associated with TBMN (also described as autosomal dominant AS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this retrospective cross-sectional study was to analyze clinical and genetic data regarding a possible genotype-phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4.    

Material and methods:

89 individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first manifestation of MH, proteinuria, ESKD, eye anomalies and hearing impairment were raised.

Results:

Individuals with monoallelic non-truncating COL4A3/COL4A4 variants reported a significantly higher prevalence of MH (46/48 (96%) vs. 14/24 (63%), p = 0.001) and proteinuria (21/48 (44%) vs. 4/24 (17%), p = 0.035) than individuals with truncating COL4A3/COL4A4 variants. Individuals with biallelic truncating COL4A3/COL4A4 variants had a significantly lower median age at first manifestation of MH (3 years vs. 6 years, p = 0.030) and proteinuria (3 years vs. 9 years, p = 0.017) than individuals with biallelic non-truncating COL4A3/COL4A4 variants. In addition, individuals with biallelic truncating variants in COL4A3/COL4A4 were significantly younger at first manifestation of proteinuria than individuals with biallelic non-truncating/truncating COL4A3/COL4A4 variants (median: 3 years vs. 9 years, p = 0.015).

Conclusions:

In this study, for the first time, an association of heterozygous non-truncating COL4A3/COL4A4 variants in TBMN/ADAS individuals with a more severe phenotype could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the literature data that biallelic truncating variants in COL4A3/COL4A4 lead to more severe clinical manifestations of AS.