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In severe cases, it can lead to frequent urinary tract infections, hydronephrosis, kidney scarring, and chronic kidney disease. Non\u2010neurogenic neurogenic bladder (NNNB) is a diagnosis of exclusion in which children develop discoordination between the detrusor smooth muscle and external urethral sphincter in the absence of neurological or obstructive lesions, resulting in severe LUTD. Historically, such disorders of voiding were thought to result from behavioral maladaptation. However, it is now increasingly recognized that some individuals may have an underlying genetic etiology for their symptoms. Here, we performed exome sequencing for five probands with NNNB or other forms of severe LUTD, and we identified two individuals with monogenic etiologies for their symptoms. One individual had a homozygous exon 9 deletion in <jats:italic>HPSE2<\/jats:italic> and another had a homozygous single amino acid deletion (p.Gly167del) in <jats:italic>ARL6<\/jats:italic>. We performed PCR experiments to identify the breakpoints of the <jats:italic>HPSE2<\/jats:italic> exon 9 deletion and implicate microhomology\u2010mediated end joining as a potential mechanism by which the deletion arose. These findings suggest that genetic testing should be considered for children with severe LUTD.<\/jats:p>","DOI":"10.1002\/ajmg.a.63859","type":"journal-article","created":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T08:26:34Z","timestamp":1725438394000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic Contributions to Lower Urinary Tract Dysfunction"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7797-4217","authenticated-orcid":false,"given":"Lilian R.","family":"Hiltebeitel","sequence":"first","affiliation":[{"name":"Division of Nephrology Boston Children's Hospital, Harvard Medical School  Boston United\u00a0States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Seltzsam","sequence":"additional","affiliation":[{"name":"Division of Nephrology Boston Children's Hospital, Harvard Medical School  Boston United\u00a0States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Nephrology Boston Children's Hospital, Harvard Medical School  Boston United\u00a0States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ted","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Urology Boston Children's Hospital, Harvard Medical School  Boston United\u00a0States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah","family":"Bolsius","sequence":"additional","affiliation":[{"name":"Division of Nephrology Boston Children's Hospital, Harvard Medical School  Boston United\u00a0States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Shalaby","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Centre of Excellence King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Department of Pediatrics, Faculty of Medicine King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sherif","family":"El Desoky","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Centre of Excellence King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Department of Pediatrics, Faculty of Medicine King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jameela A.","family":"Kari","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Centre of Excellence King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Department of Pediatrics, Faculty of Medicine King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shirlee","family":"Shril","sequence":"additional","affiliation":[{"name":"Division of Nephrology Boston Children's Hospital, Harvard Medical School  Boston 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