Abstract
Lower urinary tract dysfunction (LUTD) can manifest as a spectrum of voiding symptoms in childhood, including urinary urgency, frequency, hesitancy, and incontinence. In severe cases, it can lead to frequent urinary tract infections, hydronephrosis, kidney scarring, and chronic kidney disease. Non-neurogenic 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 HPSE2 and another had a homozygous single amino acid deletion (p.Gly167del) in ARL6. We performed PCR experiments to identify the breakpoints of the HPSE2 exon 9 deletion and implicate microhomology-mediated 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.
Keywords:
exome sequencing; lower urinary tract dysfunction; non‐neurogenic neurogenic bladder; urofacial syndrome.