家族共分离和长读序列在遗传性视网膜疾病中重新分类不确定意义变异的新作用。

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2023-08-10 DOI:10.1038/s41525-023-00366-9
Pankhuri Gupta, Kenji Nakamichi, Alyssa C Bonnell, Ryan Yanagihara, Nick Radulovich, Fuki M Hisama, Jennifer R Chao, Debarshi Mustafi
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引用次数: 0

摘要

在确定那些可能致病的基因变异时,分阶段进行基因变异是必不可少的。在常染色体隐性遗传性视网膜疾病(IRDs)中,不确定意义变异(VUS)的重分类可以为不确定的复合杂合子病例提供遗传诊断。我们报告了四个病例,其中家族共分离表明VUS存在于已知的致病变异中,这与其他支持标准一致,导致VUS重新分类为可能致病,从而为每个病例提供遗传诊断。我们还证明,在没有家庭成员进行共分离分析的单纯性患者中,靶向长读测序可以提供单倍标记的变体呼叫。这可以阐明变异是否存在于反式中,并提供先证者单独的遗传变异阶段,而无需亲代检测。在家庭成员基因检测无法提供完整基因诊断的情况下,这种新兴方法可以缓解单倍型分析的瓶颈。
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Familial co-segregation and the emerging role of long-read sequencing to re-classify variants of uncertain significance in inherited retinal diseases.

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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来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
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