Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data.

中文翻译：

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ATAD3 基因簇中反复出现的从头 NAHR 相互重复导致胆固醇和线粒体代谢紊乱的神经遗传特征。

最近的研究已经确定了由 ATAD3A 变体引起的隐性和显性形式的线粒体疾病。隐性形式包括具有由非等位基因同源重组介导的双等位基因缺失的受试者。我们报告了五名具有致命代谢疾病的无关新生儿，其特征是心肌病、角膜混浊、脑病、肌张力减退和癫痫发作，其中在 ATAD3 基因座处发现了单等位基因相互重复。断点连接片段的分析表明，这些 67 kb 杂合重复可能是由 ATAD3A 外显子 11 和 ATAD3C 外显子 7 中高序列同一性区域的非等位基因同源重组介导的。在重组连接处，复制等位基因产生融合基因从 ATAD3A 和 ATAD3C，其蛋白质产物缺乏关键功能残基。来自两个受影响个体的成纤维细胞分析表明融合基因产物表达且稳定。这些细胞显示出与严重 ATAD3A 缺乏症个体相似的胆固醇和线粒体 DNA 组织紊乱。我们假设融合蛋白通过显性失活机制起作用，导致这种致命的线粒体疾病。我们的数据描述了这种疾病的分子诊断，扩展了与 ATAD3 基因座结构变异相关的临床谱，并确定了 ATAD3 基因簇变异的第三种突变机制。这些结果进一步肯定了散发性疾病性状中的结构变异诱变机制，强调了拷贝数分析在分子基因组诊断中的重要性，