Silvia Radenkovic1, Diego Martinelli2, Yuebo Zhang3, Graeme J Preston3, Arianna Maiorana2, Alessandra Terracciano2, Maria Lisa Dentici4, Elisa Pisaneschi5, Antonio Novelli5, Wasantha Ranatunga3, Anna N Ligezka3, Bart Ghesquière6, David R Deyle3, Tamas Kozicz3, Filippo Pinto E Vairo3, Peter Witters7, Eva Morava8. 1. Department of Clinical Genomics, Mayo Clinic, Rochester, MN; Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium; Metabolomics Expertise Center, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: silvia.radenkovic@kuleuven.be. 2. Division of Metabolism, Department of Pediatrics Specialties, Bambino Gesù Children's Research Hospital, Rome, Italy. 3. Department of Clinical Genomics, Mayo Clinic, Rochester, MN. 4. Medical Genetics Unit, Bambino Gesù Children Hospital IRCCS, Rome, Italy. 5. Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital IRCCS, Rome, Italy. 6. Metabolomics Expertise Center, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium. 7. Metabolic Center, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium. 8. Department of Clinical Genomics, Mayo Clinic, Rochester, MN; Metabolic Center, University Hospitals Leuven, Leuven, Belgium; Department of Medical Genetics, Medical School, University of Pécs, Pecs, Hungary. Electronic address: Morava-kozicz.eva@mayo.edu.
Abstract
PURPOSE: TRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities. METHODS: Exome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients' blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics. RESULTS: All 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites. CONCLUSION: We identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.
PURPOSE: TRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities. METHODS: Exome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients' blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics. RESULTS: All 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites. CONCLUSION: We identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.