de Laat Paul, Janssen Mirian C H, Alston Charlotte L, Taylor Robert W, Rodenburg Richard J T, Smeitink Jan A M
Radboud University Medical Center Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands.
Radboud University Medical Center Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands; Radboud University Medical Center, Department of Internal Medicine, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands.
BBA Clin. 2016 Apr 29;6:19-24. doi: 10.1016/j.bbacli.2016.04.007. eCollection 2016 Dec.
The m.3243A > G mutation is the most prevalent, disease-causing mitochondrial DNA (mtDNA) mutation. In a national cohort study of 48 families harbouring the m.3243A > G mutation, we identified three families in which the mutation appeared to occur sporadically within these families. In this report we describe these three families. Based on detailed mtDNA analysis of three different tissues using two different quantitative pyrosequencing assays with sensitivity to a level of 1% mutated mtDNA, we conclude that the m.3243A > G mutation has arisen de novo in each of these families. The symptomatic carriers presented with a variety of symptoms frequently observed in patients harbouring the m.3243A > G mutation. A more severe phenotype is seen in the de novo families compared to recent cohort studies, which might be due to reporting bias. The observation that de novo m.3243A > G mutations exist is of relevance for both diagnostic investigations and genetic counselling. Firstly, even where there is no significant (maternal) family history in patients with stroke-like episodes, diabetes and deafness or other unexplained organ dysfunction, the m.3243A > G mutation should be screened as a possible cause of the disease. Second, analysis of maternally-related family members is highly recommended to provide reliable counselling for these families, given that the m.3243A > G mutation may have arisen de novo.
m.3243A＞G突变是最常见的致病性线粒体DNA（mtDNA）突变。在一项对48个携带m.3243A＞G突变的家族进行的全国队列研究中，我们发现其中有三个家族的该突变似乎是在家族内部散发出现的。在本报告中，我们描述这三个家族。通过使用两种对1%突变mtDNA水平敏感的不同定量焦磷酸测序分析方法，对三种不同组织进行详细的mtDNA分析，我们得出结论，m.3243A＞G突变在这些家族中均为新发突变。有症状的携带者表现出了携带m.3243A＞G突变的患者中常见的各种症状。与最近的队列研究相比，新发突变家族中观察到了更严重的表型，这可能是由于报告偏倚所致。新发m.3243A＞G突变的存在这一观察结果对诊断研究和遗传咨询均具有重要意义。首先，即使在患有中风样发作、糖尿病和耳聋或其他不明原因器官功能障碍的患者中没有显著的（母系）家族病史，也应筛查m.3243A＞G突变作为可能的病因。其次，鉴于m.3243A＞G突变可能是新发的，强烈建议对母系相关家庭成员进行分析，以便为这些家族提供可靠的咨询。
