IntroductionUrofacial, or Ochoa, syndrome (UFS) is an autosomal recessive disease featuring a dyssynergic bladder with detrusor smooth muscle contracting against an undilated outflow tract. It also features an abnormal grimace. Half of individuals with UFS carry biallelic variants inHPSE2, whereas other rare families carry variants inLRIG2.LRIG2is immunodetected in pelvic ganglia sending autonomic axons into the bladder. Moreover,Lrig2mutant mice have abnormal urination and abnormally patterned bladder nerves. We hypothesized that peripheral neurogenic defects underlieLRIG2-associated bladder dysfunction.MethodsWe describe a new family withLRIG2-associated UFS and studiedLrig2homozygous mutant mice withex vivophysiological analyses.ResultsThe index case presented antenatally with urinary tract (UT) dilatation, and postnatally had urosepsis and functional bladder outlet obstruction. He had the grimace that, together with UT disease, characterizes UFS. AlthoughHPSE2sequencing was normal, he carried a homozygous, predicted pathogenic,LRIG2stop variant (c.1939C>T; p.Arg647∗).Lrig2mutant mice had enlarged bladders.Ex vivophysiology experiments showed neurogenic smooth muscle relaxation defects in the outflow tract, containing the urethra adjoining the bladder, and in detrusor contractility. Moreover, there were nuanced differences in physiological outflow tract defects between the sexes.ConclusionPutting this family in the context of all reported UT disease-associatedLRIG2variants, the full UFS phenotype occurs with biallelic stop or frameshift variants, but missense variants lead to bladder-limited disease. Our murine observations support the hypothesis that UFS is a genetic autonomic neuropathy of the bladder affecting outflow tract and bladder body function.