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Abstract：
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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
目的：我们的报告描述了临床，遗传,在研究的第5年，在先天性糖基化障碍（FCDGC）自然病史队列中纳入分子证实的先天性糖基化障碍（CDG）参与者的生化特征。
方法：我们将已知或疑似CDG的个体纳入FCDGC自然史研究，对CDG的所有遗传原因进行多中心前瞻性和回顾性自然史研究。我们对2019年10月至2023年11月同意参加FCDGC自然历史研究（5U54NS115198）的确诊CDG参与者的基线研究访问数据进行了横断面分析。
结果：133名受试者同意FCDGC自然史研究。其中,280个独特的个体具有与CDG的诊断一致的可用遗传数据。这280人在2019年10月8日至2023年11月29日期间被纳入研究。一百四十一名(50.4%)是女性，男性139人(49.6%)。入学时的平均年龄为10.1岁和6.5岁，分别,范围为0.22至71.4年。该队列包括患有N-连接蛋白糖基化疾病的个体（57％），糖基磷脂酰肌醇锚定障碍（GPI锚定）（15％），高尔基稳态疾病，贩运和运输(12%)，dolichol代谢紊乱（5%），多种途径障碍（6%），其他（5%）。导致诊断的最常见症状是发育迟缓/残疾（77％）。其次是低张力（56％）和进食困难（42％）。首次相关症状和诊断之间的平均和中位时间为2.7年和0.8年，分别。我们队列中百分之百的人在基线就诊时存在发育差异/残疾，其次是97%的神经系统受累，91%有胃肠道（GI）/肝脏受累，88%有肌肉骨骼受累。在NijmegenProgressionCDG评定量表（NPCRS）上对个体疾病的严重程度进行了评分，其中27％的评分被归类为轻度，44%中度，29%严重。在有N-连接蛋白糖基化缺陷的个体中,83％的数据显示碳水化合物缺乏转铁蛋白（CDT）分析为1型模式，包括82/84例PMM2-CDG患者，6%的2型模式，类型1和类型2模式均为1％，正常或非特异性模式为10％。百分之百的高尔基稳态和贩运缺陷的个体在CDT分析中显示出2型模式，而高尔基运输缺陷在73%的情况下表现出II型模式，7%的1型模式，20%有正常或非特异性模式。使用ACMG标准将记录的大多数变体分类为致病性或可能致病性。对于大多数变体，预测的分子结果是错误的，其次是无义和剪接位点，大多数诊断是以常染色体隐性遗传模式遗传的，但包括所有主要核遗传的疾病。
结论：FCDGC自然历史研究是建立未来研究的重要资源，改善临床护理，并为临床试验做好准备。这是FCDGC自然史研究的CDG参与者的第一个概述。
方法：我们将已知或疑似CDG的个体纳入FCDGC自然史研究，对CDG的所有遗传原因进行多中心前瞻性和回顾性自然史研究。我们对2019年10月至2023年11月同意参加FCDGC自然历史研究（5U54NS115198）的确诊CDG参与者的基线研究访问数据进行了横断面分析。
结果：133名受试者同意FCDGC自然史研究。其中,280个独特的个体具有与CDG的诊断一致的可用遗传数据。这280人在2019年10月8日至2023年11月29日期间被纳入研究。一百四十一名(50.4%)是女性，男性139人(49.6%)。入学时的平均年龄为10.1岁和6.5岁，分别,范围为0.22至71.4年。该队列包括患有N-连接蛋白糖基化疾病的个体（57％），糖基磷脂酰肌醇锚定障碍（GPI锚定）（15％），高尔基稳态疾病，贩运和运输(12%)，dolichol代谢紊乱（5%），多种途径障碍（6%），其他（5%）。导致诊断的最常见症状是发育迟缓/残疾（77％）。其次是低张力（56％）和进食困难（42％）。首次相关症状和诊断之间的平均和中位时间为2.7年和0.8年，分别。我们队列中百分之百的人在基线就诊时存在发育差异/残疾，其次是97%的神经系统受累，91%有胃肠道（GI）/肝脏受累，88%有肌肉骨骼受累。在NijmegenProgressionCDG评定量表（NPCRS）上对个体疾病的严重程度进行了评分，其中27％的评分被归类为轻度，44%中度，29%严重。在有N-连接蛋白糖基化缺陷的个体中,83％的数据显示碳水化合物缺乏转铁蛋白（CDT）分析为1型模式，包括82/84例PMM2-CDG患者，6%的2型模式，类型1和类型2模式均为1％，正常或非特异性模式为10％。百分之百的高尔基稳态和贩运缺陷的个体在CDT分析中显示出2型模式，而高尔基运输缺陷在73%的情况下表现出II型模式，7%的1型模式，20%有正常或非特异性模式。使用ACMG标准将记录的大多数变体分类为致病性或可能致病性。对于大多数变体，预测的分子结果是错误的，其次是无义和剪接位点，大多数诊断是以常染色体隐性遗传模式遗传的，但包括所有主要核遗传的疾病。
结论：FCDGC自然历史研究是建立未来研究的重要资源，改善临床护理，并为临床试验做好准备。这是FCDGC自然史研究的CDG参与者的第一个概述。
