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Neurogenetics
Short report
TRAPPC2L-related disorder: first homozygous protein-truncating variant and further delineation of the phenotype
  1. Mario Abaji1,2,
  2. Cécile Mignon-Ravix2,
  3. Svetlana Gorokhova1,2,
  4. Pierre Cacciagli3,
  5. Jérémie Mortreux4,
  6. Florence Molinari2,
  7. Brigitte Chabrol5,
  8. Sabine Sigaudy1,
  9. Laurent Villard1,2,
  10. Florence Riccardi2,6
  1. 1 Génétique Médicale, AP-HM, Marseille, France
  2. 2 MMG, U1251, Inserm, Aix-Marseille Universite, Marseille, France
  3. 3 CRB, TAC, Assistance Publique Hopitaux de Marseille, Marseille, France
  4. 4 Service de Génétique, Eurofins Biomnis, Lyon, France
  5. 5 Neuropédiatrie, AP-HM, Marseille, France
  6. 6 Génétique Médicale, Centre Hospitalier Intercommunal Toulon - La Seyne-sur-Mer, Toulon, France
  1. Correspondence to Dr Florence Riccardi, Service de Génétique Médicale, Hôpital Sainte Musse, CHITS, Toulon, 83056, France; florence.riccardi{at}ch-toulon.fr

Abstract

The TRAPP (TRAfficking Protein Particle) complexes are evolutionarily conserved tethering factors involved in the intracellular transport of vesicles for secretion and autophagy processes. Pathogenic variants in 8 genes (of 14) encoding TRAPP proteins are involved in ultra-rare human diseases, called TRAPPopathies. Seven of them are autosomal recessive neurodevelopmental disorders with overlapping phenotypes. Since 2018, two homozygous missense variants in TRAPPC2L have been reported in five individuals from three unrelated families with early-onset and progressive encephalopathy, with episodic rhabdomyolysis. We now describe the first pathogenic protein-truncating variant in the TRAPPC2L gene found at a homozygous state in two affected siblings. This report provides key genetic evidence invaluable to establishing the gene-disease relationship for this gene and important insights into the TRAPPC2L phenotype. Regression, seizures and postnatal microcephaly initially described are not constant features. Acute episodes of infection do not contribute to the neurological course. HyperCKaemia is part of the clinical picture. Thus, TRAPPC2L syndrome is mainly characterised by a severe neurodevelopmental disorder and a variable degree of muscle involvement, suggesting that it belongs to the clinical entity of rare congenital muscular dystrophies.

  • Genetics, Medical
  • Neuromuscular Diseases
  • Mutation
  • Mental Disorders

https://doi.org/10.1136/jmg-2022-108677

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    Footnotes

    • Twitter @mario_obj, @FlorenceRicc

    • MA and CM-R contributed equally.

    • Contributors FR, MA and CM-R drafted and wrote the manuscript in consultation with all authors. FR, SS and BC provided clinical care. CM-R, PC and FM performed research WES analyses. MA, FR, SS and BC performed clinical and pathological phenotyping. SG, JM, FM, LV and BC contributed with interpretation and discussion of results. FR, MA and CM-R generated figures and supplementaries. MA and CM-R are the first coauthors as they equally contributed to this work. FR coordinated the study. LV provided financial support for the research analysis.

    • Funding This study was funded by Fondation Aix-Marseille Universite (AMX-19-IET-007).

    • Competing interests FR and SS are members of expertise centres of the French national network AnDDI-Rares and the European reference network ITHACA. FR has received funding from the Excellence Initiative of Aix-Marseille University - A*Midex a French “Investissements d’Avenir programme”- Institute MarMaRa AMX-19-IET-007” to carry out research as part of a PhD.

    • 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.