Screening copy number variations in 35 unsolved inherited retinal disease families.

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY
Human Genetics Pub Date : 2024-02-01 Epub Date: 2024-01-29 DOI:10.1007/s00439-023-02631-4
Xiaozhen Liu, Hehua Dai, Genlin Li, Ruixuan Jia, Xiang Meng, Shicheng Yu, Liping Yang, Jing Hong
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引用次数: 0

Abstract

The purpose of this study was to screen Copy Number Variations (CNVs) in 35 unsolved Inherited Retinal Dystrophy (IRD) families. Initially, next generation sequencing, including a specific Hereditary Eye Disease Enrichment Panel or Whole exome sequencing, was employed to screen (likely) pathogenic Single-nucleotide Variants (SNVs) and small Insertions and Deletions (indels) for these cases. All available SNVs and indels were further validated and co-segregation analyses were performed in available family members by Sanger sequencing. If not, after excluding deep intronic variants, Multiplex ligation-dependent probe amplification (MLPA), quantitative fluorescence PCR (QF-PCR) and Sanger sequencing were employed to screen CNVs. We determined that 18 probands who had heterozygous SNVs/indels or whose parents were not consanguineous but had homozygous SNVs/indels in autosomal recessive IRDs genes had CNVs in another allele of these genes, 11 families had disease-causing hemizygous CNVs in X-linked IRD genes, 6 families had (likely) pathogenic heterozygous CNVs in PRPF31 gene. Of 35 families, 33 different CNVs in 16 IRD-associated genes were detected, with PRPF31, EYS and USH2A the most common disease-causing gene in CNVs. Twenty-six and 7 of them were deletion and duplication CNVs, respectively. Among them, 14 CNVs were first reported in this study. Our research indicates that CNVs contribute a lot to IRDs, and screening of CNVs substantially increases the diagnostic rate of IRD. Our results emphasize that MLPA and QF-PCR are ideal methods to validate CNVs, and the novel CNVs reported herein expand the mutational spectrums of IRDs.

Abstract Image

筛查 35 个未解决的遗传性视网膜疾病家族的拷贝数变异。
这项研究的目的是在35个未解决的遗传性视网膜营养不良(IRD)家族中筛选拷贝数变异(CNV)。最初,研究人员采用新一代测序技术(包括特定的遗传性眼病富集面板或全外显子组测序)来筛选这些病例的(可能)致病性单核苷酸变异(SNV)以及小的插入和缺失(indels)。通过桑格测序法对所有可用的 SNV 和吲哚进行进一步验证,并在可用的家庭成员中进行共分离分析。如果没有,则在排除深部内含子变异后,采用多重连接依赖性探针扩增(MLPA)、定量荧光 PCR(QF-PCR)和 Sanger 测序来筛选 CNV。我们发现,18 个在常染色体隐性 IRDs 基因中存在杂合 SNVs/indels 或父母非近亲但存在同源 SNVs/indels 的病例在这些基因的另一个等位基因中存在 CNVs,11 个家族在 X 连锁 IRD 基因中存在致病的半杂合 CNVs,6 个家族在 PRPF31 基因中存在(可能)致病的杂合 CNVs。在35个家族中,16个IRD相关基因中发现了33个不同的CNV,其中PRPF31、EYS和USH2A是CNV中最常见的致病基因。其中26个和7个分别为缺失和重复CNV。其中,14 个 CNV 在本研究中首次报道。我们的研究表明,CNVs 在 IRD 中的作用很大,对 CNVs 的筛查可大大提高 IRD 的诊断率。我们的研究结果表明,MLPA和QF-PCR是验证CNVs的理想方法,本文报道的新型CNVs扩展了IRD的突变谱。
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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
期刊介绍: Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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