Pathogenic 12-kb copy-neutral inversion in syndromic intellectual disability identified by high-fidelity long-read sequencing
Pathogenic 12-kb copy-neutral inversion in syndromic intellectual disability identified by high-fidelity long-read sequencing
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DOI：
10.1016/j.ygeno.2020.10.038
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发表时间：
2021-01-25
期刊：
影响因子：
4.4
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
--
作者：
Mizuguchi, Takeshi;Okamoto, Nobuhiko;Matsumoto, Naomichi
我们报告一对同卵双胞胎女孩综合征智力残疾谁经历外显子测序，但与阴性致病变异。为了搜索外显子组测序无法识别的变体，应用高保真长读段基因组测序（HiFi LR-GS）。在基于trio的变体过滤后，通过HiFi LR-GS精确鉴定了12-kb拷贝中性倒位。这种倒位直接破坏了两个基因，CPNE 9和BRPF 1，后者引起了我们的注意，因为致病性BRPF 1变体已在常染色体显性遗传性智力发育障碍伴畸形面容和上睑下垂（IDDDFP）中被鉴定出来，后来在双胞胎中被临床发现。基于Trio的HiFi LR-GS与单倍型定相一起揭示了12-kb倒位在母系传递的染色体上从头发生。这项研究清楚地表明，亚微观拷贝中性倒位是重要的，但往往是单基因疾病的未表征的罪魁祸首，长读段测序是非常有利的检测这种倒位参与遗传疾病。
We report monozygotic twin girls with syndromic intellectual disability who underwent exome sequencing but with negative pathogenic variants. To search for variants that are unrecognized by exome sequencing, high-fidelity long-read genome sequencing (HiFi LR-GS) was applied. A 12-kb copy-neutral inversion was precisely identified by HiFi LR-GS after trio-based variant filtering. This inversion directly disrupted two genes, CPNE9 and BRPF1, the latter of which attracted our attention because pathogenic BRPF1 variants have been identified in autosomal dominant intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP), which later turned out to be clinically found in the twins. Trio-based HiFi LR-GS together with haplotype phasing revealed that the 12-kb inversion occurred de novo on the maternally transmitted chromosome. This study clearly indicates that submicroscopic copy-neutral inversions are important but often uncharacterized culprits in monogenic disorders and that long-read sequencing is highly advantageous for detecting such inversions involved in genetic diseases.