ESPN 53rd Annual Meeting

ESPN 2021


 
Exome sequencing implicates heterozygous variants in DSTYK in functional urinary bladder disturbance
CLARA VIDIC 1 MARCIN ZANIEW 2 HOLGER THIELE 3 JANINE ALTMÜLLER 3 HEIKO REUTTER 4 ALINA HILGER 4

1- Institute of Human Genetics, University of Bonn, Germany
2- Department of Pediatrics, University of Zielona Góra, Poland
3- Cologne Center for Genomics, University of Cologne, Germany
4- Department of Pediatrics, Children’s Hospital, University of Bonn, Germany
 
Abstract:

Introduction: DSTYK encodes dual serine/threonine and tyrosine protein kinase. DSTYK has been associated with autosomal dominant congenital anomalies of the kidney and urinary tract and with autosomal-recessive hereditary spastic paraplegia. Here we report a father and his two dizygotic twin sons with a novel, heterozygous variant in DSTYK, all presenting with voiding dysfunction due to functional urinary bladder disturbance.

Materials and Methods:  We performed whole exome sequencing of the family. All three presenting clinically with hesitancy, abnormal voiding pattern and night incontinence till adolescence. In the sons cystoscopy excluded urethral valves but showed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with epilepsy. Based on the pedigree, filtering of exome data focused on rare (MAF<0.01%), autosomal-dominant variants, predicted to be deleterious, residing in highly conserved regions of the exome. Validation of prioritized variants was performed using Sanger sequencing.

Results: We identified a novel, heterozygous c.271C>A (p.Leu91Met) variant in DSTYK segregating with the disease. The amino acid is highly conserved. Rated deleterious by 3 different prediction programs (SIFT, PolyPhen, MutationTaster) and with a CADD score of 24.5, this variant was prioritized as likely disease causing.  

Conclusion: To the best of our knowledge, we describe the first familial case with autosomal dominant inherited variants in DSTYK and specific functional bladder outlet obstruction and epilepsy.