ESPN 54th Annual Meeting

ESPN 2022


 
A genetic investigation of monozygotic twins discordant for solitary functioning kidney
SANDER GROEN IN T WOUD 1 ALEXANDER HOISCHEN 3 RICHARDA DE VOER 3 MARCEL NELEN 3 WOUT FEITZ 4 NEL ROELEVELD 1 LOES VAN DER ZANDEN 1 MICHIEL SCHREUDER 2

1- RADBOUD UNIVERSITY MEDICAL CENTER, DEPARTMENT FOR HEALTH EVIDENCE, RADBOUD INSTITUTE FOR HEALTH SCIENCES, NIJMEGEN, THE NETHERLANDS
2- RADBOUDUMC AMALIA CHILDREN’S HOSPITAL, DEPARTMENT OF PEDIATRIC NEPHROLOGY, RADBOUD INSTITUTE FOR MOLECULAR LIFE SCIENCES, NIJMEGEN, THE NETHERLANDS
3- RADBOUD UNIVERSITY MEDICAL CENTER, DEPARTMENT OF HUMAN GENETICS, RADBOUD INSTITUTE FOR MOLECULAR LIFE SCIENCES, NIJMEGEN, THE NETHERLANDS
4- RADBOUDUMC AMALIA CHILDREN’S HOSPITAL, DEPARTMENT OF UROLOGY, RADBOUD INSTITUTE FOR MOLECULAR LIFE SCIENCES, NIJMEGEN, THE NETHERLANDS
 
Introduction:

The aetiology of solitary functioning kidney (SFK) is likely multifactorial, and some genetic and environmental causes have been identified. With our current understanding, however, a majority of cases cannot yet be explained. The objective of this study was to determine whether postzygotic mutations could play a role in the aetiology of SFK by investigating monozygotic twins discordant for SFK.

Material and methods:

Two monozygotic twin pairs, each consisting of one child with congenital SFK and a healthy sibling, were identified in the SOFIA study. DNA was isolated from saliva samples and exomes were captured using Twist Biosciences enrichment kits. Next, whole exome sequencing was performed with a targeted sequencing depth of 300 (NovaSeg6000, Illumina). For both twin pairs, variants present in at least 2 of the reads of the affected but not the unaffected child, as identified with GATK’s MuTect2 tool, were classified as postzygotic variants. Coding postzygotic variants were ranked for biological and technical plausibility based on literature and sequencing results, respectively.

Results:

 Exome sequencing was successful in all four samples, with mean sequencing depths between 120 and 281. In twin pair one, 17 postzygotic variants were called, of which one variant was likely to be true positive. This constitutes a synonymous variant in the VGLL4 gene, which will be confirmed using targeted sequencing. In twin pair two, 108 postzygotic variants were called. However, all variants with high biological plausibility were deemed as technical artefacts after visualization using the Integrative Genomics Viewer.

Conclusions:

 A postzygotic mutation was identified in one of two monozygotic twin pairs discordant for SFK. This variant warrants further investigation before its clinical relevance can be determined. Although no obvious causal variant was found in the current study, this novel method of studying postzygotic genetic variants could enhance our understanding of the genetic aetiology of SFK.