Milder clinical and biochemical phenotypes associated with the c.482G > A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening
Milder clinical and biochemical phenotypes associated with the c.482G > A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening
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DOI：
10.1016/j.ymgme.2017.06.011
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发表时间：
2017-09-01
影响因子：
3.8
通讯作者：
Graham, Brett H.
中科院分区：
文献类型：
--
作者：
Almannai, Mohammed;Marom, Ronit;Graham, Brett H.
简介：钴胺素C病是一种多系统疾病，具有不同的表现和发病年龄。基因型-表型相关性在这种疾病中得到了很好的认识。在这里，我们提出了一大批患有钴胺素C疾病的个体，其中一些人是C . 482g > a致病性变异（p.a g161gln）的杂合。我们比较了具有这种致病变异的个体和没有这种变异的个体的临床特征。据我们所知，这项研究代表了携带c.482G > A （p.a g161gln）致病变异的最大单一队列个体。方法：对来自21个钴胺素C病患者家庭的27例患者进行回顾性图表分析。结果：13例（48%）个体在一个等位基因上与cA82G > A （p.a g161gln）复合杂合，在另一个等位基因上与第二个致病变异复合杂合。携带c.482G > A （p.Arg161Gln）致病变异的个体出现症状较晚，代谢控制较容易。此外，他们在出生时有轻微的生化异常，这可能导致该组中有4人（31%）在新生儿筛查中被遗漏。结论：c.482G >A （p.Arg161Gln）致病性变异与轻度疾病相关。这些人可能无法得到及时的诊断，因为他们可能无法在新生儿筛查中被发现，或者因为未被识别的晚发症状。尽管症状较轻，但可能发生严重的并发症，特别是如果治疗延迟。(C) 2017爱思唯尔公司版权所有。
Introduction: Cobalamin C disease is a multisystemic disease with variable manifestations and age of onset. Genotype-phenotype correlations are well-recognized in this disorder. Here, we present a large cohort of individuals with cobalamin C disease, several of whom are heterozygous for the c.482G > A pathogenic variant (p.Arg161Gln). We compared clinical characteristics of individuals with this pathogenic variant to those who do not have this variant. To our knowledge, this study represents the largest single cohort of individuals with the c.482G > A (p.Arg161Gln) pathogenic variant.Methods: A retrospective chart review of 27 individuals from 21 families with cobalamin C disease who are followed at our facility was conducted.Results: 13 individuals (48%) are compound heterozygous with the cA82G > A (p.Arg161Gln) on one allele and a second pathogenic variant on the other allele. Individuals with the c.482G > A (p.Arg161Gln) pathogenic variant had later onset of symptoms and easier metabolic control. Moreover, they had milder biochemical abnormalities at presentation which likely contributed to the observation that 4 individuals (31%) in this group were missed by newborn screening.Conclusion: The c.482G >A (p.Arg161Gln) pathogenic variant is associated with milder disease. These individuals may not receive a timely diagnosis as they may not be identified on newborn screening or because of unrecognized, late onset symptoms. Despite the milder presentation, significant complications can occur, especially if treatment is delayed. (C) 2017 Elsevier Inc. All rights reserved.