BACKGROUND Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases. METHODS Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology. RESULTS We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay. CONCLUSIONS These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases.

中文翻译：

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染色体间模板转换作为一种新的分子机制，可印制与Temple综合征相关的摄动。

背景技术染色体内重复（TRP）可通过基因剂量效应，基因破坏，位置效应或融合基因形成来促进疾病病因。近来，已证明与拷贝数中性基因组间隔相邻并具有纯合性（ROH）的合子后从头重复出现可导致单亲等位基因分离（UPD）。这些复杂的基因组重排（CGR）的基因组结构显示出一致的反向三联模式，其侧翼为重复（DUP-TRP / INV-DUP），重复由单端复制修复过程中的重复DNA复制体模板转换机制形成，如果是双链DNA（seDNA），则ROH来源于同源或非姐妹染色单体模板转换。据推测，这些CGR可能会导致携带者遗传异常，这是由于拷贝数变异区内的剂量敏感基因定位，等位基因的等位基因纯合性导致了ROH区内的常染色体隐性（AR）疾病性状，或烙印相关疾病。方法在这里，我们报告了一个家族，其中受影响的受试者携带从头开始的2.2 Mb TRP，然后携带42.2 Mb的ROH，并且其临床特征与与14号染色体孕妇UPD（UPD（14）mat）相关的特征相重叠。UPD（14）mat可以引起临床表型特征，从而可以诊断Temple综合征。然后，通过高密度的定制aCGH，全基因组范围的单核苷酸多态性（SNP）和甲基化阵列，外显子组测序（ES），以及牛津纳米孔长读测序技术。结果我们通过先证者中的多种正交基因组技术证实了假定的DUP-TRP / INV-DUP结构。染色体14上已知的差异甲基化区域（DMR）的甲基化状态表明该受试者表现出UPD（14）mat的典型甲基化模式。与这些分子发现一致的是，其临床特征与在Temple Temple综合征中观察到的那些特征重叠，包括语音延迟。结论这些数据提供了实验证据，表明在人类中，三重复会导致节段性UPD和印记疾病。重要的是，基因型/表型分析进一步揭示了由基于复制的突变机制产生的后合子产生的复杂结构变体，有助于扩大已知遗传综合症的临床表型。从机制上讲，此类事件可能会使传播遗传学产生畸变，从而导致在只有一个亲本作为携带者的基因座处发生纯合，并引起印迹疾病。