RT Journal Article SR Electronic T1 Ureteropelvic junction obstruction with primary lymphoedema associated with CELSR1 variants JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 1161 OP 1168 DO 10.1136/jmg-2023-109171 VO 60 IS 12 A1 Alpaslan, Murat A1 Mestré-Godin, Sandrine A1 Lay, Aurélie A1 Giacalone, Guido A1 Helaers, Raphaël A1 Adham, Salma A1 Kovacsik, Hélène A1 Guillemard, Sophie A1 Mercier, Erick A1 Boon, Laurence A1 Revencu, Nicole A1 Brouillard, Pascal A1 Quere, Isabelle A1 Vikkula, Miikka YR 2023 UL http://jmg.bmj.com/content/60/12/1161.abstract AB Background Primary 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 protein Cadherin Epidermal Growth Factor Laminin G Seven-pass G-type Receptor 1 (CELSR1) variants linked to PL.Methods We investigated 742 index patients from our PL cohort using exome sequencing.Results We identified nine variants predicted to cause CELSR1 loss 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 with CELSR1 before. CELSR1 is 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, CELSR1 may be the long-sought gene for the renal defects.Conclusion PL associated with a renal anomaly suggests a CELSR1-related cause.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The datasets supporting the current study have not been deposited in a public repository because data are not public due to privacy laws on patients. Some of the data may be requested by contacting to corresponding author. Source data for online supplemental table 2 and online supplemental table 3 in the paper are available on DOI: 10.1111/cge.13622, DOI: 10.1186/s13221-016-0035-5, DOI: 10.1002/ajmg.a.61269, DOI: 10.21203/rs.3.rs-1299738/v1 and DOI: 10.1097/MD.0000000000026307.