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Kidney Week

Abstract: SA-PO815

Genetic Contributions to Lower Urinary Tract Dysfunction

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hiltebeitel, Lily, Boston Children's Hospital, Boston, Massachusetts, United States
  • Seltzsam, Steve, Boston Children's Hospital, Boston, Massachusetts, United States
  • Wang, Chunyan, Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Proper bladder function requires coordinated interactions between the urothelium, detrusor smooth muscle, urethral sphincter, and neuronal circuitry. Historically, severe voiding dysfunction, or the so-called non-neurogenic neurogenic bladder, was attributed to urinary withholding and behavioral maladaptation. However, several monogenic causes of lower urinary tract dysfunction have been identified, leading to a paradigm shift in our understanding of this disease. The aim of this study is to better understand the genetic landscape of voiding dysfunction in children.

Methods

We performed exome sequencing (ES) in 16 individuals with non-neurogenic neurogenic bladder or voiding dysfunction. Individuals with obstructive uropathy, spinal cord lesions, or a known neurological cause for their disease were excluded. In addition, we reviewed ES results from 24 individuals with non-neurogenic neurogenic bladder who have been described in our prior studies (van der Ven JASN 2018; Seltzsam Genet Med 2022) and analyzed data for variants in 76 candidate genes purported to play a role in urothelial signaling, detrusor function, or neuronal innervation of the bladder.

Results

We identified a pathogenic variant in 3/16 (18%) individuals with lower urinary tract dysfunction. Two individuals had homozygous variants in HPSE2 (c.1099-2A>G, essential splice; exon9 deletion) and one individual had a homozygous variant in a phenocopy gene ARL6 (c. 500_502delGAG, p.Gly67del), which causes a renal-retinal ciliopathy. Of the 24 individuals described in our prior publications, four had known pathogenic variants, of which three were homozygous pathogenic variants in HPSE2 (c.457C>T, p.Arg153*; c.1099-2A>G, essential splice; exon 9 deletion). In total, 7/40 (17%) of our cohort were found to have a monogenic cause for their disease. Notably, two individuals in this cohort had homozygous deletions in exon 9 in HPSE2, which were identified only through manual inspection of ES data.

Conclusion

Variants in HPSE2 are a common cause of non-neurogenic neurogenic bladder in our consanguineous cohort. Structural variants in HPSE2 were identified in our cohort and have been described previously (Beaman Front Genet 13:896125, 2022), underscoring the importance of incorporating CNV analyses into genetic testing for individuals with lower urinary tract or voiding dysfunction.

Funding

  • NIDDK Support