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Genotype-phenotype correlations
Original research
Ureteropelvic junction obstruction with primary lymphoedema associated with CELSR1 variants
  1. Murat Alpaslan1,
  2. Sandrine Mestré-Godin2,3,
  3. Aurélie Lay2,
  4. Guido Giacalone4,
  5. Raphaël Helaers1,
  6. Salma Adham2,3,
  7. Hélène Kovacsik2,
  8. Sophie Guillemard5,
  9. Erick Mercier3,6,
  10. Laurence Boon1,7,
  11. Nicole Revencu7,
  12. Pascal Brouillard1,
  13. Isabelle Quere2,3,
  14. Miikka Vikkula1,8
  1. 1 Human Molecular Genetics, de Duve Institute, Brussels, Belgium
  2. 2 Department of vascular medicine, CHU Montpellier, Montpellier, France
  3. 3 IDESP - Institut Desbrest d’Épidémiologie et de Santé Publique, Montpellier, France
  4. 4 Department of Lymphatic Surgery, VASCERN PPL European Reference Centre, General Hospital Sint-Maarten, Mechelen, Belgium
  5. 5 Department of Nuclear Medicine, Montpellier Regional Cancer Institute, Montpellier, France
  6. 6 Hematology Laboratory, University Hospital Centre Nimes, Nimes, France
  7. 7 Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Centre, Cliniques universitaires Saint-Luc, Brussels, Belgium
  8. 8 WELBIO, WEL Research Institute, Wavre, Belgium
  1. Correspondence to Professor Miikka Vikkula, Human Molecular Genetics, de Duve Institute, Brussels 1200, Belgium; miikka.vikkula{at}uclouvain.be

Abstract

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.

  • Vascular Diseases
  • Hemic and Lymphatic Diseases
  • Genetics
  • Human Genetics

Data availability statement

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.

https://doi.org/10.1136/jmg-2023-109171

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    Data availability statement

    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.

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    Footnotes

    • Twitter @MiikkaVikkula

    • MA and SM-G contributed equally.

    • IQ and MV contributed equally.

    • Contributors Conceptualisation: MA, PB, IQ and MV; data curation: MA, RH, PB and MV; formal analysis; resources: SM-G, AL, GG, SA, HK, SG, EM, LB, NR and IQ; software: RH; supervision: IQ and MV; writing (original draft): MA; writing (review and editing): MA, SM-G, PB, IQ and MV; guarantor: MV.

    • Funding This study was financially supported by la Région wallonne dans le cadre du financement de l’axe stratégique FRFS-WELBIO (WELBIO-CR-2019C-06), by the Fonds de la Recherche Scientifique (grants T.0026.14 and T.0247.19), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the European Union’s Horizon 2020 research and innovation programme (under the Marie Skłodowska-Curie grant agreement number 814316), of which MA is one of the ESRs, the Leducq Foundation Networks of Excellence Program grant 'ReVAMP' (LFCR grant number 21CVD03) and the European Union’s Horizon 2020 research and innovation programme (under grant agreement number 874708 (Theralymph) (all to MV)).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.