Ureteropelvic junction obstruction with primary lymphoedema associated withCELSR1variants

BackgroundPrimary lymphoedema (PL) is a chronic, debilitating disease caused by developmental and functional defects of the lymphatic system. It is marked by an accumulation of interstitial fluid, fat and tissue fibrosis. There is no cure. More than 50 genes and genetic loci have been linked to PL. We sought to study systematically cell polarity signalling proteinCadherin Epidermal Growth Factor Laminin G Seven-pass G-type Receptor 1(CELSR1) variants linked to PL.MethodsWe investigated 742 index patients from our PL cohort using exome sequencing.ResultsWe identified nine variants predicted to causeCELSR1loss of function. Four of them were tested for nonsense-mediated mRNA decay, but none was observed. Most of the truncated CELSR1 proteins would lack the transmembrane domain, if produced. The affected individuals had puberty/late-onset PL on lower extremities. The variants had a statistically significant difference in penetrance between female patients (87%) and male patients (20%). Eight variant carriers had a kidney anomaly, mostly in the form of ureteropelvic junction obstruction, which has not been associated withCELSR1before.CELSR1is located in the 22q13.3 deletion locus of the Phelan-McDermid syndrome. As variable renal defects are often seen in patients with the Phelan-McDermid syndrome,CELSR1may be the long-sought gene for the renal defects.ConclusionPL associated with a renal anomaly suggests aCELSR1-related cause.