Exome sequencing implicates a novel heterozygous missense variant in DSTYK in autosomal dominant lower urinary tract dysfunction and mild hereditary spastic paraparesis

Clara Vidic; Marcin Zaniew; Szymon Jurga; Holger Thiele; Heiko Reutter; Alina C Hilger

doi:10.1186/s40348-021-00122-y

Exome sequencing implicates a novel heterozygous missense variant in DSTYK in autosomal dominant lower urinary tract dysfunction and mild hereditary spastic paraparesis

Mol Cell Pediatr. 2021 Oct 4;8(1):13. doi: 10.1186/s40348-021-00122-y.

Authors

Clara Vidic^#¹, Marcin Zaniew^#², Szymon Jurga³, Holger Thiele⁴, Heiko Reutter⁵, Alina C Hilger^{6

7}

Affiliations

¹ Institute of Human Genetics, University of Bonn, Bonn, Germany.
² Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland.
³ Department of Neurology, University of Zielona Góra, Zielona Góra, Poland.
⁴ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁵ Department of Neonatology and Paediatric Intensive Care, University Hospital Erlangen, Erlangen, Germany.
⁶ Institute of Human Genetics, University of Bonn, Bonn, Germany. alina.hilger@uni-bonn.de.
⁷ Department of Pediatrics, Children's Hospital, University of Bonn, Bonn, Germany. alina.hilger@uni-bonn.de.

^# Contributed equally.

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 type 23. Here, we report a father and his two dizygotic twin sons carrying a novel heterozygous missense variant in DSTYK, presenting with early onset lower urinary tract dysfunction due to dysfunctional voiding. Moreover, in the later course of the disease, both sons presented with bilateral spasticity in their lower limbs, brisk reflexes, and absence seizures.

Materials and methods: Exome sequencing in the affected father and his affected sons was performed. The sons presented clinically with urinary hesitancy, dysfunctional voiding, and night incontinence till adolescence, while the father reported difficulty in voiding. In the sons, cystoscopy excluded urethral valves and revealed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with absence epilepsy in early childhood. 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.

Results: Exome analysis identified a novel, heterozygous missense variant (c.271C>A (p.Leu91Met)) in DSTYK segregating with the disease. In silico prediction analyses uniformly rated the variant to be deleterious suggesting the variant to be disease-causing in the family.

Conclusion: To the best of our knowledge, this is the first report of early onset dysfunctional voiding, seizures, and bilateral spasticity of the lower limbs associated with a novel heterozygous dominant missense variant in DSTYK.

Keywords: CAKUT; DSTYK; Epilepsy; Functional urinary bladder disturbance; HSP23; Hereditary spastic paraparesis.