Pajusalu Sander, Vals Mari-Anne, Serrano Mercedes, Witters Peter, Cechova Anna, Honzik Tomáš, Edmondson Andrew C, Ficicioglu Can, Barone Rita, De Lonlay Pascale, Bérat Claire-Marine, Vuillaumier-Barrot Sandrine, Lam Christina, Patterson Marc C, Janssen Mirian C H, Martins Esmeralda, Quelhas Dulce, Sykut-Cegielska Jolanta, Mousa Jehan, Urreizti Roser, McWilliams Peter, Vernhes Frederique, Plotkin Horacio, Morava Eva, Õunap Katrin
Genetics and Personalized Medicine Clinic, Tartu University Hospital, L. Puusepa Street 2, Tartu, Estonia.
Department of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, L. Puusepa Street 2, Tartu, Estonia.
Hum Mutat. 2024 Oct 3;2024:8813121. doi: 10.1155/2024/8813121. eCollection 2024.
We report on the largest single dataset of patients with PMM2-CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% ( = 80) of participants, followed by p.Pro113Leu (21.2%, = 29), and p.Phe119Leu (12.4%, = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease-associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2-CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. NCT03173300.
我们报告了参与一项正在进行的国际多中心自然史研究的最大规模的磷酸甘露糖变位酶2型先天性糖基化障碍（PMM2-CDG）患者单一数据集，该研究收集基因、临床和生物学信息，以评估与既往研究的相似性，报告新发现，并另外研究潜在的基因型/表型相关性。共有137名参与者拥有完整的基因型信息，代表60种独特变异，其中最常见的是p.Arg141His，在58.4%（n = 80）的参与者中出现，其次是p.Pro113Leu（21.2%，n = 29）和p.Phe119Leu（12.4%，n = 17），这与既往研究一致。有趣的是，报告了6种新变异，包括5种错义变异（p.Pro20Leu、p.Tyr64Ser、p.Phe68Cys、p.Tyr76His和p.Arg238His）和1种移码变异（c.696del p.Ala233Argfs∗100）。通过奈梅亨进展性CDG评分量表（NPCRS）以及生化参数对患者表型进行特征描述，其中最一致失调的是凝血因子，特别是抗凝血酶（117例中有93例，79.5%低于正常水平），此外还有因子XI和蛋白C活性。根据疾病相关突变的预测致病机制对患者基因型进行分类，其中大多数位于PMM2酶的催化/激活、折叠或二聚化区域。采用两种不同方法来揭示基因型/表型关系。第一种方法仅根据预测的致病机制对基因型进行特征描述，并揭示生化参数的相关变化，这在仅使用NPCRS时并不明显，涉及催化/激活、二聚化、折叠且无蛋白变异。第二种方法根据预测的致病机制和/或与一组严重无功能变异配对时的个体变异对基因型进行特征描述，并揭示与NPCRS和生化参数的相关性，表明p.Cys241Ser与较轻疾病相关，而p.Val231Met、二聚化和折叠变异与更严重疾病相关。尽管此前已证明确定PMM2-CDG全面的基因型/表型关系具有挑战性，但本研究中更大的样本量以及纳入生化参数，为遗传学与疾病的相互作用提供了新见解。NCT03173300。
