Neurogenic defects underlie functional bladder outflow tract obstruction associated with biallelic variants in LRIG2

Urinary tract malformations account for half of all children with kidney failure, and some have defined monogenic causes. One such disorder is urofacial, or Ochoa, syndrome (UFS), an autosomal recessive disease featuring a dyssynergic bladder with detrusor smooth muscle contracting against an undilated outflow tract. Incomplete voiding predisposes to urosepsis and kidney failure. Half of individuals with UFS carry biallelic variants in HPSE2, whereas some carry variants in LRIG2 (leucine rich repeats and immunoglobulin like domains 2). We report one new kindred where the index case presented with fetal hydronephrosis and postnatally had urosepsis and functional bladder outlet obstruction. He had the grimace that, together with urinary tract disease, characterizes UFS. While HPSE2 sequencing was normal, he carried a homozygous, predicted pathogenic, stop variant (c.1939C>T; p.Arg647*) in LRIG2. Hypothesizing that neurogenic defects underlie LRIG2-associated bladder dysfunction, we studied Lrig2 homozygous mutant mice. Juveniles had enlarged bladders and ex vivo physiology experiments showed neurogenic defects in outflow tract relaxation. Mutants also displayed abnormal detrusor contractility. Moreover, there were nuanced differences in physiological defects between the sexes. The current case emphasizes that urinary tract disease in UFS begins before birth. Putting this family in the context of all reported urinary tract disease-associated LRIG2 variants, the urinary and facial phenotype of UFS occurs with biallelic putative loss of function variants, but missense variants lead to bladder-limited disease without the grimace. Finally, our murine observations support the hypothesis that UFS is a genetic autonomic neuropathy of the bladder affecting outflow tract and bladder body function.