ESPN 53rd Annual Meeting

ESPN 2021


 
NO CLEAR INDICATION FOR DIGENIC INHERITANCE IN 60 INDIVIDUALS WITH DISEASE-CAUSING VARIANTS IN COL4A3, COL4A4 OR COL4A5 AND IN A MENDELIAN GENOMICS EXOME DATABASE OF MORE THAN 22,000 INDIVIDUALS
JASMINA ĆOMIć 1 KORBINIAN M. RIEDHAMMER 1 ROMAN GÜNTHNER 2 PATRICK RICHTHAMMER 1 HANNES SIMMENDINGER 1 DONALD KIEFFER 1 LUTZ RENDERS 2 UWE HEEMANN 2 MATTHIAS C. BRAUNISCH 2 UTE MOOG 3 THOMAS MEITINGER 1 JULIA HOEFELE 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- INSTITUTE OF HUMAN GENETICS, HEIDELBERG UNIVERSITY, HEIDELBERG, GERMANY
 
Introduction:

Disease-causing variants in COL4A3-5 are known to be associated with type-IV-collagen-related nephropathy, comprising Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). Initial symptoms of individuals with AS are microscopic hematuria (MH) followed by proteinuria leading to end-stage renal disease (ESRD). Extrarenal manifestations like hearing impairment and eye abnormalities can additionally be observed in AS. In contrast, individuals with TBMN mostly present with MH, only some of these individuals develop ESRD. Digenic inheritance has been proposed as causative for type-IV-collagen-related nephropathy and discussed as a possible aggravating factor of the phenotype in type-IV-collagen-related nephropathy. However, up to now only little and inconclusive information concerning this topic can be found in the literature.

Material and methods:

60 index cases, in whom exome sequencing had been performed and with (likely) pathogenic variant(s) in COL4A3-5 (summarized to “disease-causing variant”), were reanalyzed for additional (likely) pathogenic variants in COL4A3-5. Moreover, a Mendelian genomics database (Munich Exome Server) comprising 22,000 exomes was scrutinized for individuals with a combination of disease-causing variants in at least two of the three collagen genes COL4A3, COL4A4, or COL4A5.

Results:

Of 60 reanalyzed individuals, 83% had AS phenotypically, 12% TBMN and 5% had focal segmental glomerulosclerosis. No additional disease-causing variants were identified in one of the alternate COL4A3-5 genes in these individuals. In the Munich Exome Server, only one individual with a non-renal phenotype and a combination of a heterozygous disease-causing variant in COL4A4 and COL4A5, respectively, was identified.

Conclusions:

In this study, no clear indication for digenic inheritance could be observed implicating that this phenomenon might be very rare and not that common than postulated in the literature. Future research on digenic inheritance in type-IV-collagen-related nephropathy should focus on statistic evidence from case-control studies and experimental proof of functional impact of digenic variants in COL4A3-5.