ESPN 54th Annual Meeting

ESPN 2022


 
Novel syndrome: Craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome associated with TSEN2 mutation
NUR CANPOLAT 1 DINGXIAO LIU 2 EMINE ATAYAR 3 SEHA SAYGILI 1 NAZLI SILA KARA 4 TRUDI A. WESTFALL 5 QIONG DING 2 BARTLEY J. BROWN 6 TERRY A. BRAUN 6 DIANE SLUSARSKI 6 KADER KARLI OGUZ 7 YASEMIN OZLUK 8 BEYHAN TUYSUZ 9 TUGBA TASTEMEL OZTURK 10 LALE SEVER 1 OSMAN UGUR SEZERMAN 4 REZAN TOPALOGLU 10 SALIM CALISKAN 1 MASSIMO ATTANASIO 2 FATIH OZALTIN 10

1- DEPARTMENT OF PEDIATRIC NEPHROLOGY, ISTANBUL UNIVERSITY-CERRAHPASA, CERRAHPASA FACULTY OF MEDICINE, ISTANBUL, TURKEY
2- CARVER COLLEGE OF MEDICINE, UNIVERSITY OF IOWA, IOWA CITY, IA
3- NEPHROGENETICS LABORATORY, DEPARTMENT OF PEDIATRIC NEPHROLOGY, HACETTEPE UNIVERSITY, FACULTY OF MEDICINE, ANKARA, TURKEY
4- BIOSTATISTICS AND MEDICAL INFORMATICS PROGRAM, FACULTY OF MEDICINE, GRADUATE SCHOOL OF HEALTH SCIENCES, ACIBADEM MEHMET ALI AYDINLAR UNIVERSITY, ISTANBUL, TURKEY
5- DEPARTMENT OF BIOLOGY, UNIVERSITY OF IOWA, IOWA CITY, IA
6- CENTER FOR BIOINFORMATICS AND COMPUTATIONAL BIOLOGY, UNIVERSITY OF IOWA, IOWA CITY, IA
7- DEPARTMENT OF RADIOLOGY, HACETTEPE UNIVERSITY FACULTY OF MEDICINE, ANKARA, TURKEY
8- DEPARTMENT OF PATHOLOGY, ISTANBUL UNIVERSITY FACULTY OF MEDICINE, ISTANBUL, TURKEY
9- DEPARTMENT OF PEDIATRIC GENETICS, ISTANBUL UNIVERSITY-CERRAHPASA, CERRAHPASA FACULTY OF MEDICINE, ISTANBUL, TURKEY
10- DEPARTMENT OF PEDIATRIC NEPHROLOGY, HACETTEPE UNIVERSITY, FACULTY OF MEDICINE, ANKARA, TURKEY
 
Introduction:

 Atypical hemolytic uremic syndrome (aHUS) is a rare and severe form of thrombotic microangiopathy (TMA). All forms of hemolytic uremic syndromes arise from vascular endothelial cell injury of the microvasculature of the kidney and other organs through complement-dependent or complement-independent mechanisms. The underlying genetic etiology has not been identified in 30% to 40% of all cases of aHUS, which indicates that there are still unknown etiologies.

Material and methods:

 We described six children from four consanguineous pedigrees, affected with microcephaly and craniofacial malformations, severe growth failure, intellectual retardation, and aHUS that progressed to end stage kidney disease requiring kidney replacement therapy within the first decade of life. Whole exome sequencing (WES) was perfomed to identify underlying genetic etiology.  

Results:

Our research identified a homozygous intronic variant in the gene TSEN2 (tRNA splicing endonuclease subunit 2) associated with this undescribed new syndrome. Bulk RNA sequencing of peripheral blood cells of four affected individuals revealed abnormal tRNA transcripts, indicating an alteration of the tRNA biogenesis. Morpholino-mediated skipping of exon 10 of tsen2 in zebrafish produced phenotypes similar to human patients. 

Conclusions:

 We have identified a novel syndrome accompanied by aHUS that suggests the existence of a link between tRNA biology and vascular endothelium homeostasis. We propose to name it TRACK syndrome (TSEN2 Related Atypical hemolytic uremic syndrome, Craniofacial malformations, Kidney failure).