Familial co-segregation and the emerging role of long-read sequencing to re-classify variants of uncertain significance in inherited retinal diseases.
Familial co-segregation and the emerging role of long-read sequencing to re-classify variants of uncertain significance in inherited retinal diseases.
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DOI：
10.1038/s41525-023-00366-9
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发表时间：
2023-08-10
影响因子：
5.3
通讯作者：
Mustafi, Debarshi
中科院分区：
文献类型：
--
作者：
Gupta, Pankhuri;Nakamichi, Kenji;Bonnell, Alyssa C. C.;Yanagihara, Ryan;Radulovich, Nick;Hisama, Fuki M. M.;Chao, Jennifer R. R.;Mustafi, Debarshi
计量遗传变异对于确定可能引起疾病的变体至关重要。在常染色体隐性遗传性视网膜疾病（IRDS）中，重新分类不确定意义（VUS）可以在不确定的复合杂合子病例中提供遗传诊断。我们报告了四个案例，其中家族性共隔离证明了驻留到已知的致病变体中的VU，该变异与其他支持标准一致，导致VUS将VUS重新分类为可能的致病性，从而在每种情况下都提供了遗传诊断。我们还在单纯性患者中证明，没有与家庭成员进行共隔离分析，该分析有针对性的长阅读测序可以提供单封装的变体呼叫。这可以阐明变体是否存在于反式中并提供单独的概率的遗传变异阶段，而无需父母测试。在家庭成员的基因检测不可行无法提供完整的遗传诊断的情况下，这种新兴方法可以减轻单倍型分析的瓶颈。
Phasing genetic variants is essential in determining those that are potentially disease-causing. In autosomal recessive inherited retinal diseases (IRDs), reclassification of variants of uncertain significance (VUS) can provide a genetic diagnosis in indeterminate compound heterozygote cases. We report four cases in which familial co-segregation demonstrated a VUS resided in trans to a known pathogenic variant, which in concert with other supporting criteria, led to the reclassification of the VUS to likely pathogenic, thereby providing a genetic diagnosis in each case. We also demonstrate in a simplex patient without access to family members for co-segregation analysis that targeted long-read sequencing can provide haplotagged variant calling. This can elucidate if variants reside in trans and provide phase of genetic variants from the proband alone without parental testing. This emerging method can alleviate the bottleneck of haplotype analysis in cases where genetic testing of family members is unfeasible to provide a complete genetic diagnosis.
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影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
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作者：
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通讯作者：
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DOI：
10.1073/pnas.1913179117
发表时间：
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作者：
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