Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Am J Hum Genet. 2022 May 5;109(5):961-966. doi: 10.1016/j.ajhg.2022.03.011. Epub 2022 Apr 8.
The well-established manifestation of mitochondrial mutations in functional cardiac disease (e.g., mitochondrial cardiomyopathy) prompted the hypothesis that mitochondrial DNA (mtDNA) sequence and/or copy number (mtDNAcn) variation contribute to cardiac defects in congenital heart disease (CHD). MtDNAcns were calculated and rare, non-synonymous mtDNA mutations were identified in 1,837 CHD-affected proband-parent trios, 116 CHD-affected singletons, and 114 paired cardiovascular tissue/blood samples. The variant allele fraction (VAF) of heteroplasmic variants in mitochondrial RNA from 257 CHD cardiovascular tissue samples was also calculated. On average, mtDNA from blood had 0.14 rare variants and 52.9 mtDNA copies per nuclear genome per proband. No variation with parental age at proband birth or CHD-affected proband age was seen. mtDNAcns in valve/vessel tissue (320 ± 70) were lower than in atrial tissue (1,080 ± 320, p = 6.8E-21), which were lower than in ventricle tissue (1,340 ± 280, p = 1.4E-4). The frequency of rare variants in CHD-affected individual DNA was indistinguishable from the frequency in an unaffected cohort, and proband mtDNAcns did not vary from those of CHD cohort parents. In both the CHD and the comparison cohorts, mtDNAcns were significantly correlated between mother-child, father-child, and mother-father. mtDNAcns among people with European (mean = 52.0), African (53.0), and Asian haplogroups (53.5) were calculated and were significantly different for European and Asian haplogroups (p = 2.6E-3). Variant heteroplasmic fraction (HF) in blood correlated well with paired cardiovascular tissue HF (r = 0.975) and RNA VAF (r = 0.953), which suggests blood HF is a reasonable proxy for HF in heart tissue. We conclude that mtDNA mutations and mtDNAcns are unlikely to contribute significantly to CHD risk.
线粒体突变在功能性心脏疾病（如线粒体心肌病）中的明显表现促使人们假设线粒体 DNA（mtDNA）序列和/或拷贝数（mtDNAcn）的变化导致了先天性心脏病（CHD）中的心脏缺陷。在 1837 个 CHD 受影响的先证者-父母三体型、116 个 CHD 受影响的单体型和 114 对心血管组织/血液样本中计算了 mtDNAcn，并鉴定了罕见的非同义 mtDNA 突变。还计算了来自 257 个 CHD 心血管组织样本的线粒体 RNA 中异质体变体的变异等位基因分数（VAF）。平均而言，血液中的 mtDNA 每个核基因组每例先证者有 0.14 个罕见变体和 52.9 个 mtDNA 拷贝。没有观察到与先证者出生时父母年龄或受影响的先证者年龄有关的变化。瓣膜/血管组织中的 mtDNAcn（320 ± 70）低于心房组织（1080 ± 320，p = 6.8E-21），后者低于心室组织（1340 ± 280，p = 1.4E-4）。受影响个体 DNA 中罕见变体的频率与未受影响队列的频率无法区分，并且先证者 mtDNAcn 与 CHD 队列父母的 mtDNAcn 没有差异。在 CHD 组和对照组中，母子、父子和母子之间的 mtDNAcn 均呈显著相关性。计算了具有欧洲（平均值= 52.0）、非洲（53.0）和亚洲单倍群的人的 mtDNAcn，并发现欧洲和亚洲单倍群之间的 mtDNAcn 有显著差异（p = 2.6E-3）。血液中的变体异质体分数（HF）与配对心血管组织 HF（r = 0.975）和 RNA VAF（r = 0.953）高度相关，这表明血液 HF 是心脏组织 HF 的合理替代物。我们得出结论，mtDNA 突变和 mtDNAcn 不太可能显著增加 CHD 的风险。
