Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort.

Autor: Lam C; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA; Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. Electronic address: ctlam2@uw.edu., Scaglia F; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Hong KongSAR, China., Berry GT; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Larson A; Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, USA., Sarafoglou K; Divisions of Endocrinology and Genetics-Metabolism, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, USA., Andersson HC; Hayward Genetics Center, Dept Pediatrics Tulane School of Medicine, USA., Sklirou E; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Tan QKG; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Starosta RT; Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, USA., Sadek M; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Wolfe L; Medical Genetic Branch, National Human Genome Research Institute, Bethesda, MD, USA., Horikoshi S; Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA., Ali M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Barone R; Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute, IRCCS, Troina, Italy., Campbell T; Division of Genetic Medicine, Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA., Chang IJ; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA; Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA., Coles K; Child Health Research Enterprise, Children's Hospital Colorado, USA., Cook E; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA., Eklund EA; Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Pediatrics, Skåne University Hospital, Lund, Sweden., Engelhardt NM; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA., Freeman M; Division of Medical Genetics and Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, USA., Friedman J; Division of Neurosciences and Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA; Rady Children's Hospital, San Diego, CA, USA., Fu DYT; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Botzo G; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Rawls B; Texas Children's Hospital, Houston, TX, USA., Hernandez C; Child Health Research Enterprise, Children's Hospital Colorado, USA., Johnsen C; Department of Pediatrics and Adolescent Medicine, University Medical Centre, Göttingen, Germany., Keller K; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA., Kramer S; Pediatric Clinical Research Services, University of Minnesota, Minneapolis, MN, USA., Kuschel B; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Leshinski A; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Martinez-Duncker I; Laboratorio de Glicobiología Humana y Diagnóstico Molecular, Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mexico., Mazza GL; Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ, USA., Mercimek-Andrews S; Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada., Miller BS; Division of Endocrinology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA., Muthusamy K; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA., Neira J; Department of Human Genetics, Emory University, Atlanta, GA 30322, USA., Patterson MC; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Pogorelc N; Pediatric Clinical Research Services, University of Minnesota, Minneapolis, MN, USA., Powers LN; Division of Genetic Medicine, Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA., Ramey E; Pediatric Clinical Research Services, University of Minnesota, Minneapolis, MN, USA., Reinhart M; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA., Squire A; Division of Genetic Medicine, Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA., Thies J; Division of Genetic Medicine, Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA., Vockley J; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States; Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, United States., Vreugdenhil H; Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA., Witters P; Department of Development and Regeneration, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Center for Metabolic Diseases, Department of Paediatrics, University Hospitals Leuven, Leuven, Belgium., Youbi M; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA., Zeighami A; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA., Zemet R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA., Edmondson AC; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA., Morava E; Division of Medical Genetics and Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, USA.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2024 Aug; Vol. 142 (4), pp. 108509. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1016/j.ymgme.2024.108509
Abstrakt: Objective: Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the Frontiers in Congenital Disorders of Glycosylation (FCDGC) Natural History cohort at year 5 of the study.
Methods: We enrolled individuals with a known or suspected CDG into the FCDGC Natural History Study, a multicenter prospective and retrospective natural history study of all genetic causes of CDG. We conducted a cross-sectional analysis of baseline study visit data from participants with confirmed CDG who were consented into the FCDGC Natural History Study (5U54NS115198) from October 2019 to November 2023.
Results: Three hundred thirty-three subjects consented to the FCDGC Natural History Study. Of these, 280 unique individuals had genetic data available that was consistent with a diagnosis of CDG. These 280 individuals were enrolled into the study between October 8, 2019 and November 29, 2023. One hundred forty-one (50.4%) were female, and 139 (49.6%) were male. Mean and median age at enrollment was 10.1 and 6.5 years, respectively, with a range of 0.22 to 71.4 years. The cohort encompassed individuals with disorders of N-linked protein glycosylation (57%), glycosylphosphatidylinositol anchor disorder (GPI anchor) (15%), disorders of Golgi homeostasis, trafficking and transport (12%), dolichol metabolism disorders (5%), disorders of multiple pathways (6%), and other (5%). The most frequent presenting symptom(s) leading to diagnosis were developmental delay/disability (77%), followed by hypotonia (56%) and feeding difficulties (42%). Mean and median time between first related symptom and diagnosis was 2.7 and 0.8 years, respectively. One hundred percent of individuals in our cohort had developmental differences/disabilities at the time of their baseline visit, followed by 97% with neurologic involvement, 91% with gastrointestinal (GI)/liver involvement, and 88% with musculoskeletal involvement. Severity of disease in individuals was scored on the Nijmegen Progression CDG Rating Scale (NPCRS) with 27% of scores categorized as mild, 44% moderate, and 29% severe. Of the individuals with N-linked protein glycosylation defects, 83% of those with data showed a type 1 pattern on carbohydrate deficient transferrin (CDT) analysis including 82/84 individuals with PMM2-CDG, 6% a type 2 pattern, 1% both type 1 and type 2 pattern and 10% a normal or nonspecific pattern. One hundred percent of individuals with Golgi homeostasis and trafficking defects with data showed a type 2 pattern on CDT analysis, while Golgi transport defect showed a type II pattern 73% of the time, a type 1 pattern for 7%, and 20% had a normal or nonspecific pattern. Most of the variants documented were classified as pathogenic or likely pathogenic using ACMG criteria. For the majority of the variants, the predicted molecular consequence was missense followed by nonsense and splice site, and the majority of the diagnoses are inherited in an autosomal recessive pattern but with disorders of all major nuclear inheritance included.
Discussion: The FCDGC Natural History Study serves as an important resource to build future research studies, improve clinical care, and prepare for clinical trial readiness. Herein is the first overview of CDG participants of the FCDGC Natural History Study.
Competing Interests: Declaration of competing interest The authors report no conflict of interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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