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Leveraging large-scale datasets and single cell omics data to develop a polygenic score for cisplatin-induced ototoxicity. 利用大规模数据集和单细胞 omics 数据开发顺铂诱发耳毒性的多基因评分。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-08 DOI: 10.1186/s40246-024-00679-5
Deanne Nixie R Miao, MacKenzie A P Wilke, John Pham, Feryal Ladha, Mansumeet Singh, Janilyn Arsenio, Emilia Luca, Alain Dabdoub, Wejian Yang, Jun J Yang, Britt I Drögemöller

Background: Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO and genome-wide association studies (GWAS) have highlighted the polygenicity of this adverse drug reaction. Polygenic scores (PGS), which integrate information from multiple genetic variants across the genome, offer a promising tool for the identification of individuals who are at higher risk for CIO. Integrating large-scale hearing loss GWAS data with single cell omics data holds potential to overcome limitations related to small sample sizes associated with CIO studies, enabling the creation of PGSs to predict CIO risk.

Results: We utilized a large-scale hearing loss GWAS and murine inner ear single nuclei RNA-sequencing (snRNA-seq) data to develop two polygenic scores: a hearing loss PGS (PGSHL) and a biologically informed PGS for CIO (PGSCIO). The PGSCIO included only variants which mapped to genes that were differentially expressed within cochlear cells that showed differential abundance in the murine snRNA-seq data post-cisplatin treatment. Evaluation of the association of these PGSs with CIO in our target CIO cohort revealed that PGSCIO demonstrated superior performance (P = 5.54 × 10- 5) relative to PGSHL (P = 2.93 × 10- 3). PGSCIO was also associated with CIO in our test cohort (P = 0.04), while the PGSHL did not show a significant association with CIO (P = 0.52).

Conclusion: This study developed the first PGS for CIO using a large-scale hearing loss dataset and a biologically informed filter generated from cisplatin-treated murine inner ear snRNA-seq data. This innovative approach offers new avenues for developing PGSs for pharmacogenomic traits, which could contribute to the implementation of tailored therapeutic interventions. Further, our approach facilitated the identification of specific cochlear cells that may play critical roles in CIO. These novel insights will guide future research aimed at developing targeted therapeutic strategies to prevent CIO.

背景:顺铂诱导的耳毒性(CIO)是顺铂化疗的一种常见不良反应,其特征是不可逆转的进行性双侧听力损失。除临床风险因素外,遗传变异也是导致 CIO 的原因之一,而全基因组关联研究(GWAS)则强调了这种药物不良反应的多基因性。多基因评分(PGS)整合了来自全基因组多个基因变异的信息,为识别CIO高风险个体提供了一种前景广阔的工具。将大规模听力损失 GWAS 数据与单细胞 omics 数据相结合,有可能克服与 CIO 研究相关的样本量小的局限性,从而创建预测 CIO 风险的 PGS:我们利用大规模听力损失 GWAS 和小鼠内耳单核 RNA 序列(snRNA-seq)数据开发了两种多基因评分:听力损失 PGS(PGSHL)和针对 CIO 的生物知情 PGS(PGSCIO)。PGSCIO 只包含映射到在顺铂治疗后小鼠 snRNA-seq 数据中显示出不同丰度的耳蜗细胞内差异表达基因的变异。在我们的目标 CIO 队列中评估这些 PGS 与 CIO 的关联时发现,相对于 PGSHL(P = 2.93 × 10-3),PGSCIO 表现出更优越的性能(P = 5.54 × 10-5)。在我们的测试队列中,PGSCIO 与 CIO 也有关联(P = 0.04),而 PGSHL 与 CIO 没有显著关联(P = 0.52):本研究利用大规模听力损失数据集和顺铂处理的小鼠内耳 snRNA-seq 数据生成的生物信息过滤器,首次开发了针对 CIO 的 PGS。这种创新方法为开发药物基因组特征的 PGS 提供了新途径,有助于实施量身定制的治疗干预措施。此外,我们的方法还有助于鉴定可能在 CIO 中发挥关键作用的特定耳蜗细胞。这些新颖的见解将指导未来的研究,以开发预防 CIO 的靶向治疗策略。
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引用次数: 0
Evaluating the clinical efficacy of a long-read sequencing-based approach for carrier screening of spinal muscular atrophy. 评估基于长读数测序的脊髓性肌萎缩症携带者筛查方法的临床疗效。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-29 DOI: 10.1186/s40246-024-00676-8
Ju Long, Di Cui, Chunhui Yu, Wanli Meng

Spinal muscular atrophy (SMA) is the second most common fatal genetic disease in infancy. It is caused by deletion or intragenic pathogenic variants of the causative gene SMN1, which degenerates anterior horn motor neurons and leads to progressive myasthenia and muscle atrophy. Early treatment improves motor function and prognosis in patients with SMA, but drugs are expensive and do not cure the disease. Therefore, carrier screening seems to be the most effective way to prevent SMA birth defects. In this study, we genetically analyzed 1400 samples using multiplex ligation-dependent probe amplification (MLPA) and quantitative polymerase chain reaction (qPCR), and compared the consistency of the results. We randomly selected 44 samples with consistent MLPA and qPCR results for comprehensive SMA analysis (CASMA) using a long-read sequencing (LRS)-based approach. CASMA results showed 100% consistency, visually and intuitively explained the inconsistency between exons 7 and 8 copy numbers detected by MLPA in 13 samples. A total of 16 samples showed inconsistent MLPA and qPCR results for SMN1 exon 7. CASMA was performed on all samples and the results were consistent with those of resampling for MLPA and qPCR detection. CASMA also detected an additional intragenic variant c.-39A>G in a sample with two copies of SMN1 (RT02). Finally, we detected 23 SMA carriers, with an estimated carrier rate of 1/61 in this cohort. In addition, CASMA identified the "2 + 0" carrier status of SMN1 and SMN2 in a family by analyzing the genotypes of only three samples (parents and one sibling). CASMA has great advantages over MLPA and qPCR assays, and could become a powerful technical support for large-scale screening of SMA.

脊髓性肌萎缩症(SMA)是婴儿期第二大最常见的致命遗传病。它是由致病基因 SMN1 的缺失或基因内致病变异引起的,会使前角运动神经元变性,导致进行性肌无力和肌肉萎缩。早期治疗可改善 SMA 患者的运动功能和预后,但药物昂贵且不能治愈疾病。因此,携带者筛查似乎是预防 SMA 出生缺陷的最有效方法。在本研究中,我们使用多重连接依赖性探针扩增(MLPA)和定量聚合酶链反应(qPCR)对 1400 个样本进行了基因分析,并比较了结果的一致性。我们随机选取了 44 个 MLPA 和 qPCR 结果一致的样本,采用基于长序列测序(LRS)的方法进行 SMA 综合分析(CASMA)。CASMA 结果显示出 100% 的一致性,直观地解释了 13 个样本中 MLPA 检测到的第 7 和第 8 外显子拷贝数不一致的情况。共有 16 个样本的 SMN1 第 7 号外显子的 MLPA 和 qPCR 结果不一致。对所有样本都进行了 CASMA 检测,结果与重新取样进行 MLPA 和 qPCR 检测的结果一致。CASMA 还在一个有两个 SMN1(RT02)拷贝的样本中检测到了一个额外的基因内变异 c.-39A>G。最后,我们检测到 23 个 SMA 携带者,估计该队列中的携带率为 1/61。此外,CASMA 只分析了三个样本(父母和一个兄弟姐妹)的基因型,就确定了一个家族中 SMN1 和 SMN2 的 "2 + 0 "携带者状态。与 MLPA 和 qPCR 方法相比,CASMA 具有很大的优势,可以成为大规模筛查 SMA 的有力技术支持。
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引用次数: 0
Forward-reverse mutation cycles in cancer cell lines under chemical treatments. 化学疗法下癌细胞株的正向-逆向突变周期。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-27 DOI: 10.1186/s40246-024-00661-1
Si Chen, Iram S Tyagi, Wai Kin Mat, Muhammad A Khan, Weijian Fan, Zhenggang Wu, Taobo Hu, Can Yang, Hong Xue

Spontaneous forward-reverse mutations were reported by us earlier in clinical samples from various types of cancers and in HeLa cells under normal culture conditions. To investigate the effects of chemical stimulations on such mutation cycles, the present study examined single nucleotide variations (SNVs) and copy number variations (CNVs) in HeLa and A549 cells exposed to wogonin-containing or acidic medium. In wogonin, both cell lines showed a mutation cycle during days 16-18. In acidic medium, both cell lines displayed multiple mutation cycles of different magnitudes. Genomic feature colocalization analysis suggests that CNVs tend to occur in expanded and unstable regions, and near promoters, histones, and non-coding transcription sites. Moreover, phenotypic variations in cell morphology occurred during the forward-reverse mutation cycles under both types of chemical treatments. In conclusion, chemical stresses imposed by wogonin or acidity promoted cyclic forward-reverse mutations in both HeLa and A549 cells to different extents.

我们早先曾报道过各种癌症临床样本和正常培养条件下 HeLa 细胞中的自发正向逆转突变。为了研究化学刺激对这种突变周期的影响,本研究检测了暴露于含wogonin或酸性培养基的HeLa和A549细胞中的单核苷酸变异(SNVs)和拷贝数变异(CNVs)。在 wogonin 培养基中,两种细胞系都在第 16-18 天出现突变周期。在酸性培养基中,两种细胞系都出现了多个不同程度的突变周期。基因组特征共定位分析表明,CNVs 往往发生在扩展区和不稳定区,以及启动子、组蛋白和非编码转录位点附近。此外,在两种化学处理下的正向-反向突变循环过程中,细胞形态都发生了表型变化。总之,沃戈宁或酸性物质施加的化学压力在不同程度上促进了 HeLa 和 A549 细胞的正向逆转突变循环。
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引用次数: 0
Frequency of pharmacogenomic variants affecting safety and efficacy of immunomodulators and biologics in a South Asian population from Sri Lanka. 斯里兰卡南亚人群中影响免疫调节剂和生物制剂安全性和有效性的药物基因组变异的频率。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-27 DOI: 10.1186/s40246-024-00674-w
Priyanga Ranasinghe, Chiranthi Liyanage, Nirmala Sirisena, Sandamini Liyanage, C D Nelanka Priyadarshani, D P Bhagya Hendalage, Vajira H W Dissanayake

Background: Immunomodulators are important for management of autoimmune diseases and hematological malignancies. Significant inter-individual variation in drug response/reactions exists due to genetic polymorphisms. We describe frequency of identified genetic polymorphisms among Sri Lankans.

Methods: Sri Lankan data were obtained from an anonymized database of 670 participants. Data on variants and global distribution of Minor Allele frequency (MAF) of other populations (South Asian, Ashkenazi-Jewish, East-Asian, European-Finnish, European-non-Finnish, Latino-American, African/African-American) were obtained from pharmGKB online database.

Results: SLC19A1 (rs1051266) variant had a MAF (95% CI) of 63.3% (60.7-65.9). Other common variants included FCGR3A (rs396991), MTHFR (rs1801133), ITPA (rs1127354), CYP2C9*3 (rs1057910) and NUD15*3 (rs116855232), with MAFs of 35.3% (32.7-37.9), 12.2% (10.4-13.9), 10.9% (9.2-12.6), 9.8% (8.2-11.4), 8.3% (6.8-9.8) respectively. Less commonly present variants included CYP2C9*2 (rs1799853) (2.5%[1.7-3.4]), TPMT*3C (rs1142345) (1.9%[1.1-2.6]), TPMT*3B (rs1800460) (0.2%[0-0.5]), CYP3A5*6 (rs10264272) (0.2%[0-0.4]) and CYP3A4*18 (rs28371759) (0.1%[0-0.2]). The SLC19A1 (rs1051266), NUD15*3 (rs116855232), CYP2C9*3 (rs1057910), FCGR3A (rs396991), and ITPA (rs1127354) showed significantly higher frequencies in Sri Lankans compared to many other populations, exceptions include FCGR3A in Ashkenazi-Jewish and ITPA in East-Asians. Conversely, MTHFR (rs1801133), TPMT*3B (rs1800460), and CYP2C9*2 (rs1799853) were significantly less prevalent among Sri Lankans than in  many other populations. Sri Lankans exhibited lower prevalence of TPMT*3C (rs1142345) compared to European-non-Finnish, Latino-Americans, and African/African-Americans; CYP3A4*18 (rs28371759) compared to East-Asians; and CYP3A5*6 (rs10264272) compared to African/African-Americans and Latino-Americans.

Conclusion: Sri Lankans exhibit higher frequencies in variants reducing methotrexate efficacy (SLC19A1), increasing azathioprine myelotoxicity (NUDT15), and lower frequencies in variants linked to increased azathioprine toxicity (TPMT*3B, TPMT*3C), reduced tacrolimus efficacy (CYP3A4*18), and methotrexate toxicity risk (MTHFR). Beneficial variants enhancing rituximab efficacy (FCGR3A) are more prevalent, while those reducing tacrolimus dosage (CYP3A5*6) are less common. This highlights need for targeted medication strategies to improve treatment outcomes.

背景:免疫调节剂是治疗自身免疫性疾病和血液恶性肿瘤的重要药物。由于基因多态性,个体间对药物的反应存在显著差异。我们描述了在斯里兰卡人中发现的基因多态性的频率:斯里兰卡的数据来自一个包含 670 名参与者的匿名数据库。其他人群(南亚人、犹太人、东亚人、欧洲人-芬兰人、欧洲人-非芬兰人、拉丁美洲人、非洲人/非洲裔美国人)的变异和小等位基因频率(MAF)的全球分布数据来自 pharmGKB 在线数据库:SLC19A1(rs1051266)变异的MAF(95% CI)为63.3%(60.7-65.9)。其他常见变异包括 FCGR3A (rs396991)、MTHFR (rs1801133)、ITPA (rs1127354)、CYP2C9*3 (rs1057910) 和 NUD15*3 (rs116855232),其 MAF 为 35.3%(32.7-37.9)、12.2%(10.4-13.9)、10.9%(9.2-12.6)、9.8%(8.2-11.4)、8.3%(6.8-9.8)。较少出现的变异包括 CYP2C9*2 (rs1799853) (2.5%[1.7-3.4])、TPMT*3C (rs1142345) (1.9%[1.1-2.6])、TPMT*3B(rs1800460)(0.2%[0-0.5])、CYP3A5*6(rs10264272)(0.2%[0-0.4])和 CYP3A4*18(rs28371759)(0.1%[0-0.2])。与许多其他人群相比,SLC19A1 (rs1051266)、NUD15*3 (rs116855232)、CYP2C9*3 (rs1057910)、FCGR3A (rs396991)和 ITPA (rs1127354)在斯里兰卡人中的频率明显较高,例外情况包括阿什肯纳齐犹太人中的 FCGR3A 和东亚人中的 ITPA。相反,MTHFR(rs1801133)、TPMT*3B(rs1800460)和 CYP2C9*2(rs1799853)在斯里兰卡人中的流行率明显低于许多其他人群。与欧洲-非芬兰人、拉丁美洲人和非洲/非裔美国人相比,斯里兰卡人的 TPMT*3C (rs1142345) 患病率较低;与东亚人相比,斯里兰卡人的 CYP3A4*18 (rs28371759) 患病率较低;与非洲/非裔美国人和拉丁美洲人相比,斯里兰卡人的 CYP3A5*6 (rs10264272) 患病率较低:结论:斯里兰卡人在降低甲氨蝶呤疗效(SLC19A1)和增加硫唑嘌呤骨髓毒性(NUDT15)的变异中表现出较高的频率,而在与增加硫唑嘌呤毒性(TPMT*3B、TPMT*3C)、降低他克莫司疗效(CYP3A4*18)和甲氨蝶呤毒性风险(MTHFR)相关的变异中表现出较低的频率。提高利妥昔单抗疗效的有益变异(FCGR3A)更为普遍,而降低他克莫司剂量的变异(CYP3A5*6)则较少见。这突显出需要有针对性的用药策略来改善治疗效果。
{"title":"Frequency of pharmacogenomic variants affecting safety and efficacy of immunomodulators and biologics in a South Asian population from Sri Lanka.","authors":"Priyanga Ranasinghe, Chiranthi Liyanage, Nirmala Sirisena, Sandamini Liyanage, C D Nelanka Priyadarshani, D P Bhagya Hendalage, Vajira H W Dissanayake","doi":"10.1186/s40246-024-00674-w","DOIUrl":"10.1186/s40246-024-00674-w","url":null,"abstract":"<p><strong>Background: </strong>Immunomodulators are important for management of autoimmune diseases and hematological malignancies. Significant inter-individual variation in drug response/reactions exists due to genetic polymorphisms. We describe frequency of identified genetic polymorphisms among Sri Lankans.</p><p><strong>Methods: </strong>Sri Lankan data were obtained from an anonymized database of 670 participants. Data on variants and global distribution of Minor Allele frequency (MAF) of other populations (South Asian, Ashkenazi-Jewish, East-Asian, European-Finnish, European-non-Finnish, Latino-American, African/African-American) were obtained from pharmGKB online database.</p><p><strong>Results: </strong>SLC19A1 (rs1051266) variant had a MAF (95% CI) of 63.3% (60.7-65.9). Other common variants included FCGR3A (rs396991), MTHFR (rs1801133), ITPA (rs1127354), CYP2C9*3 (rs1057910) and NUD15*3 (rs116855232), with MAFs of 35.3% (32.7-37.9), 12.2% (10.4-13.9), 10.9% (9.2-12.6), 9.8% (8.2-11.4), 8.3% (6.8-9.8) respectively. Less commonly present variants included CYP2C9*2 (rs1799853) (2.5%[1.7-3.4]), TPMT*3C (rs1142345) (1.9%[1.1-2.6]), TPMT*3B (rs1800460) (0.2%[0-0.5]), CYP3A5*6 (rs10264272) (0.2%[0-0.4]) and CYP3A4*18 (rs28371759) (0.1%[0-0.2]). The SLC19A1 (rs1051266), NUD15*3 (rs116855232), CYP2C9*3 (rs1057910), FCGR3A (rs396991), and ITPA (rs1127354) showed significantly higher frequencies in Sri Lankans compared to many other populations, exceptions include FCGR3A in Ashkenazi-Jewish and ITPA in East-Asians. Conversely, MTHFR (rs1801133), TPMT*3B (rs1800460), and CYP2C9*2 (rs1799853) were significantly less prevalent among Sri Lankans than in  many other populations. Sri Lankans exhibited lower prevalence of TPMT*3C (rs1142345) compared to European-non-Finnish, Latino-Americans, and African/African-Americans; CYP3A4*18 (rs28371759) compared to East-Asians; and CYP3A5*6 (rs10264272) compared to African/African-Americans and Latino-Americans.</p><p><strong>Conclusion: </strong>Sri Lankans exhibit higher frequencies in variants reducing methotrexate efficacy (SLC19A1), increasing azathioprine myelotoxicity (NUDT15), and lower frequencies in variants linked to increased azathioprine toxicity (TPMT*3B, TPMT*3C), reduced tacrolimus efficacy (CYP3A4*18), and methotrexate toxicity risk (MTHFR). Beneficial variants enhancing rituximab efficacy (FCGR3A) are more prevalent, while those reducing tacrolimus dosage (CYP3A5*6) are less common. This highlights need for targeted medication strategies to improve treatment outcomes.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment. 对耐药性精神分裂症进行全基因组关联分析,以发现变体并进行多基因评估。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-27 DOI: 10.1186/s40246-024-00673-x
Hasan Çağın Lenk, Elise Koch, Kevin S O'Connell, Robert Løvsletten Smith, Ibrahim A Akkouh, Srdjan Djurovic, Ole A Andreassen, Espen Molden

Background: Treatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively.

Results: We identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10-7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10-6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively.

Conclusions: We report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

背景:耐药性精神分裂症(TRS)的广义定义是对适当治疗的反应不足,与疾病负担的大幅增加有关。氯氮平是唯一获准用于治疗 TRS 的药物,与其他药物相比,它对总体症状的临床疗效更佳,是非典型抗精神病药物的雏形。利培酮是另一种非典型抗精神病药物,具有更明显的多巴胺2拮抗作用,常用于治疗精神分裂症。在此,我们对接受氯氮平(TRS)与利培酮(非 TRS)治疗的患者进行了一项全基因组关联研究,并调查了精神分裂症的单基因变异和/或多基因风险评分是否与 TRS 状态相关。我们假设,接受氯氮平与利培酮治疗的患者可能会表现出不同的神经生物学表型,这些表型与这两种药物的药理学特征相匹配,并且可以用遗传差异来解释。研究对象(n = 1286)是在 2005 年至 2022 年期间从常规治疗药物监测(TDM)服务中招募的。曾检测到氯氮平与利培酮的血清浓度(无氯氮平的TDM史)分别定义为TRS组(n = 478)和非TRS组(n = 808):我们发现TRS与LINC00523基因中的一个常见变异存在提示性关联,其显著性略低于全基因组阈值(rs79229764 C > T, OR = 4.89; p = 1.8 × 10-7)。精神分裂症的多基因风险评分与 TRS 显著相关(OR = 1.4,p = 2.1 × 10-6)。在精神分裂症供体(n = 214;CommonMind Consortium)的大量死后脑样本中,基因表达分析表明,rs79229764变异等位基因可能参与了GPR88和PUDP的调控,而GPR88和PUDP分别在纹状体神经传递和智力障碍中发挥作用:我们报告了rs79229764位点与TRS的提示性遗传关联,并表明精神分裂症的遗传责任与TRS呈正相关。这些结果为今后的后续研究提供了一个候选位点,以阐明 TRS 的分子基础。我们的研究结果进一步证明了单变异和多基因关联分析对预测 TRS 的价值。
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引用次数: 0
The regulatory landscape of interacting RNA and protein pools in cellular homeostasis and cancer. 细胞稳态和癌症中相互影响的 RNA 和蛋白质池的调控格局。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-27 DOI: 10.1186/s40246-024-00678-6
Carlos J Gallardo-Dodd, Claudia Kutter

Biological systems encompass intricate networks governed by RNA-protein interactions that play pivotal roles in cellular functions. RNA and proteins constituting 1.1% and 18% of the mammalian cell weight, respectively, orchestrate vital processes from genome organization to translation. To date, disentangling the functional fraction of the human genome has presented a major challenge, particularly for noncoding regions, yet recent discoveries have started to unveil a host of regulatory functions for noncoding RNAs (ncRNAs). While ncRNAs exist at different sizes, structures, degrees of evolutionary conservation and abundances within the cell, they partake in diverse roles either alone or in combination. However, certain ncRNA subtypes, including those that have been described or remain to be discovered, are poorly characterized given their heterogeneous nature. RNA activity is in most cases coordinated through interactions with RNA-binding proteins (RBPs). Extensive efforts are being made to accurately reconstruct RNA-RBP regulatory networks, which have provided unprecedented insight into cellular physiology and human disease. In this review, we provide a comprehensive view of RNAs and RBPs, focusing on how their interactions generate functional signals in living cells, particularly in the context of post-transcriptional regulatory processes and cancer.

生物系统包含由 RNA 蛋白相互作用支配的错综复杂的网络,这些网络在细胞功能中发挥着关键作用。RNA和蛋白质分别占哺乳动物细胞重量的1.1%和18%,它们协调着从基因组组织到翻译的重要过程。迄今为止,厘清人类基因组的功能部分一直是一项重大挑战,尤其是非编码区,但最近的发现已开始揭示非编码 RNA(ncRNA)的一系列调控功能。虽然 ncRNA 的大小、结构、进化保护程度和在细胞内的丰度各不相同,但它们单独或组合在一起发挥着不同的作用。然而,某些 ncRNA 亚型,包括那些已经描述或尚未发现的 ncRNA 亚型,因其异质性而特征不清。在大多数情况下,RNA 的活性是通过与 RNA 结合蛋白(RBPs)的相互作用来协调的。目前,人们正努力准确地重建 RNA-RBP 调控网络,这为我们深入了解细胞生理学和人类疾病提供了前所未有的视角。在这篇综述中,我们将全面介绍 RNA 和 RBPs,重点探讨它们之间的相互作用如何在活细胞中产生功能信号,尤其是在转录后调控过程和癌症方面。
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引用次数: 0
Study of adiponectin gene (rs1501299) polymorphism and serum adiponectin level in patients with primary knee osteoarthritis. 原发性膝关节骨性关节炎患者脂肪连接蛋白基因(rs1501299)多态性与血清脂肪连接蛋白水平的研究
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-23 DOI: 10.1186/s40246-024-00670-0
Rehab Elnemr, Mowaffak Moustafa Abd El Hamid, Raghda Saad Zaghloul Taleb, Naylan Fayez Wahba Khalil, Sherine Mahmoud El-Sherif

Background: We aimed to study, for the first time in the Egyptian population, the relationship between the serum adiponectin level in knee osteoarthritis (KOA) patients and its correlation with clinical, radiological, and ultrasonographic characteristics. Additionally, investigate the relationship between the adiponectin (ADIPOQ) gene rs1501299 (+ 276G/T) polymorphism and KOA susceptibility and severity.

Methods: This case-control study enrolled 40 patients with primary KOA and 40 matched controls. All patients underwent physical examination of the knee, pain assessment using the visual analogue scale (VAS), and functional evaluation by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Severity of KOA was assessed by Kellgren Lawrence (KL) grading scale and ultrasonography grading systems. Serum adiponectin levels and adiponectin (ADIPOQ) gene single nucleotide polymorphism (SNP) (rs1501299) genotyping were done for all patients and controls.

Results: The study included 40 patients with primary symptomatic KOA and 40 controls with comparable age, sex, and body mass index. The genotype of the rs1501299 (+ 276G/T) polymorphism of the ADIPOQ gene was determined using TaqMan allelic discrimination. An enzyme-linked immunosorbent test was used to measure the level of serum adiponectin. The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score was used to assess functional capability, while the visual analogue scale was utilised to assess knee pain. Using the Kellgren-Lawrence (KL) grading method and global femoral cartilage (GFC) ultrasound grading, the severity of KOA was assessed. No significant differences between patients and controls as regards the genotype distributions and allele frequencies (p = 0.400, p = 0.507, respectively) of ADIPOQ gene rs1501299 (+ 276G/T) polymorphism. Furthermore, serum adiponectin level was significantly higher in the patients compared to healthy subjects (p < 0.001). Additionally, adiponectin level had a significant negative correlation with disease severity as evaluated by KL and GFC grading (r=-0.351, p = 0.027 and r=-0.397, p = 0.011, respectively).

Conclusions: The ADIPOQ gene rs1501299 (+ 276G/T) polymorphism was not associated with KOA severity or vulnerability. The level of adiponectin considerably reduced as the severity of KOA rose, indicating that adiponectin may have a preventive effect in KOA.

背景:我们旨在首次在埃及人群中研究膝关节骨性关节炎(KOA)患者血清脂肪连接蛋白水平及其与临床、放射学和超声波特征之间的关系。此外,还研究了脂肪连接蛋白(ADIPOQ)基因 rs1501299 (+ 276G/T)多态性与 KOA 易感性和严重程度之间的关系:这项病例对照研究共纳入 40 名原发性 KOA 患者和 40 名匹配对照者。所有患者均接受了膝关节体格检查、视觉模拟量表(VAS)疼痛评估以及西安大略和麦克马斯特大学骨关节炎指数(WOMAC)功能评估。KOA 的严重程度通过 Kellgren Lawrence(KL)分级表和超声波分级系统进行评估。对所有患者和对照组进行了血清脂肪连素水平和脂肪连素(ADIPOQ)基因单核苷酸多态性(SNP)(rs1501299)基因分型:研究对象包括 40 名有原发性症状的 KOA 患者和 40 名年龄、性别和体重指数相当的对照组。采用 TaqMan 等位基因辨别法测定 ADIPOQ 基因 rs1501299(+ 276G/T)多态性的基因型。使用酶联免疫吸附试验测量血清脂肪连素的水平。西安大略和麦克马斯特大学骨关节炎(WOMAC)评分用于评估功能能力,视觉模拟量表用于评估膝关节疼痛。采用凯尔格伦-劳伦斯(Kellgren-Lawrence,KL)分级法和全局股骨头软骨(GFC)超声分级法评估 KOA 的严重程度。ADIPOQ基因rs1501299(+ 276G/T)多态性的基因型分布和等位基因频率在患者和对照组之间无明显差异(分别为p = 0.400和p = 0.507)。此外,与健康受试者相比,患者的血清脂肪连蛋白水平明显更高(p 结论:ADIPOQ基因rs1501299(+ 276G/T)多态性与患者的血清脂肪连蛋白水平有关:ADIPOQ 基因 rs1501299 (+ 276G/T) 多态性与 KOA 的严重程度或易感性无关。随着 KOA 严重程度的增加,脂肪连通素的水平明显降低,这表明脂肪连通素可能对 KOA 有预防作用。
{"title":"Study of adiponectin gene (rs1501299) polymorphism and serum adiponectin level in patients with primary knee osteoarthritis.","authors":"Rehab Elnemr, Mowaffak Moustafa Abd El Hamid, Raghda Saad Zaghloul Taleb, Naylan Fayez Wahba Khalil, Sherine Mahmoud El-Sherif","doi":"10.1186/s40246-024-00670-0","DOIUrl":"10.1186/s40246-024-00670-0","url":null,"abstract":"<p><strong>Background: </strong>We aimed to study, for the first time in the Egyptian population, the relationship between the serum adiponectin level in knee osteoarthritis (KOA) patients and its correlation with clinical, radiological, and ultrasonographic characteristics. Additionally, investigate the relationship between the adiponectin (ADIPOQ) gene rs1501299 (+ 276G/T) polymorphism and KOA susceptibility and severity.</p><p><strong>Methods: </strong>This case-control study enrolled 40 patients with primary KOA and 40 matched controls. All patients underwent physical examination of the knee, pain assessment using the visual analogue scale (VAS), and functional evaluation by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Severity of KOA was assessed by Kellgren Lawrence (KL) grading scale and ultrasonography grading systems. Serum adiponectin levels and adiponectin (ADIPOQ) gene single nucleotide polymorphism (SNP) (rs1501299) genotyping were done for all patients and controls.</p><p><strong>Results: </strong>The study included 40 patients with primary symptomatic KOA and 40 controls with comparable age, sex, and body mass index. The genotype of the rs1501299 (+ 276G/T) polymorphism of the ADIPOQ gene was determined using TaqMan allelic discrimination. An enzyme-linked immunosorbent test was used to measure the level of serum adiponectin. The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score was used to assess functional capability, while the visual analogue scale was utilised to assess knee pain. Using the Kellgren-Lawrence (KL) grading method and global femoral cartilage (GFC) ultrasound grading, the severity of KOA was assessed. No significant differences between patients and controls as regards the genotype distributions and allele frequencies (p = 0.400, p = 0.507, respectively) of ADIPOQ gene rs1501299 (+ 276G/T) polymorphism. Furthermore, serum adiponectin level was significantly higher in the patients compared to healthy subjects (p < 0.001). Additionally, adiponectin level had a significant negative correlation with disease severity as evaluated by KL and GFC grading (r=-0.351, p = 0.027 and r=-0.397, p = 0.011, respectively).</p><p><strong>Conclusions: </strong>The ADIPOQ gene rs1501299 (+ 276G/T) polymorphism was not associated with KOA severity or vulnerability. The level of adiponectin considerably reduced as the severity of KOA rose, indicating that adiponectin may have a preventive effect in KOA.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11421100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic history and biological adaptive landscape of the Tujia people inferred from shared haplotypes and alleles 从共享单倍型和等位基因推断土家族人的遗传历史和生物适应景观
IF 4.5 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-18 DOI: 10.1186/s40246-024-00672-y
Jing Chen, Mengge Wang, Shuhan Duan, Qingxin Yang, Yan Liu, Mengyang Zhao, Qiuxia Sun, Xiangping Li, Yuntao Sun, Haoran Su, Zhiyong Wang, Yuguo Huang, Jie Zhong, Yuhang Feng, Xiaomeng Zhang, Guanglin He, Jiangwei Yan
High-quality genomic datasets from under-representative populations are essential for population genetic analysis and medical relevance. Although the Tujia are the most populous ethnic minority in southwestern China, previous genetic studies have been fragmented and only partially reveal their genetic diversity landscape. The understanding of their fine-scale genetic structure and potentially differentiated biological adaptive features remains nascent. This study aims to explore the demographic history and genetic architecture related to the natural selection of the Tujia people, focusing on a meta-Tujia population from the central regions of the Yangtze River Basin. Population genetic analyses conducted on the meta-Tujia people indicate that they occupy an intermediate position in the East Asian North-South genetic cline. A close genetic affinity was identified between the Tujia people and neighboring Sinitic-speaking populations. Admixture models suggest that the Tujia can be modeled as a mixture of northern and southern ancestries. Estimates of f3/f4 statistics confirmed the presence of ancestral links to ancient Yellow River Basin millet farmers and the BaBanQinCen-related groups. Furthermore, population-specific natural selection signatures were explored, revealing highly differentiated functional variants between the Tujia and southern indigenous populations, including genes associated with hair morphology (e.g., EDAR) and skin pigmentation (e.g., SLC24A5). Additionally, both shared and unique selection signatures were identified among ethnically diverse but geographically adjacent populations, highlighting their extensive admixture and the biological adaptations introduced by this admixture. The study unveils significant population movements and genetic admixture among the Tujia and other ethno-linguistically diverse East Asian groups, elucidating the differentiated adaptation processes across geographically diverse populations from the current genetic landscape.
来自代表性不足人群的高质量基因组数据集对于人群遗传分析和医学相关性至关重要。虽然土家族是中国西南部人口最多的少数民族,但以往的遗传学研究都很零散,只能部分揭示其遗传多样性景观。人们对土家族精细的遗传结构和潜在的生物适应性差异特征的了解仍处于起步阶段。本研究以长江流域中部地区的元土家族人群为研究对象,旨在探索土家族的人口历史和与自然选择相关的遗传结构。对元土家族进行的种群遗传分析表明,他们在东亚南北遗传系中处于中间位置。研究发现,土家族人与邻近的讲汉化语言的人群之间有着密切的遗传亲缘关系。混血模型表明,土家族可被视为北方和南方祖先的混血。对 f3/f4 统计量的估计证实了土家族祖先与古代黄河流域的粟农和与八盘秦岑有关的族群之间存在联系。此外,研究还探讨了特定种群的自然选择特征,发现了土家族和南方土著种群之间高度分化的功能变异,包括与毛发形态(如 EDAR)和皮肤色素沉着(如 SLC24A5)相关的基因。此外,在种族不同但地理位置相邻的人群中,还发现了共同和独特的选择特征,突显了他们的广泛混血以及这种混血所带来的生物适应性。该研究揭示了土家族和其他民族语言多样的东亚群体之间显著的人口迁移和遗传混杂,从当前的遗传景观中阐明了地理多样群体之间的差异化适应过程。
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引用次数: 0
Whole-exome sequencing to identify causative variants in juvenile sudden cardiac death 通过全基因组测序确定青少年心脏性猝死的致病变异基因
IF 4.5 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-16 DOI: 10.1186/s40246-024-00657-x
Martina Modena, Alberto Giannoni, Alberto Aimo, Paolo Aretini, Nicoletta Botto, Simona Vittorini, Andrea Scatena, Diana Bonuccelli, Marco Di Paolo, Michele Emdin
Juvenile sudden cardiac death (SCD) remains unexplained in approximately 40% of cases, leading to a significant emotional burden for the victims’ families and society. Comprehensive investigations are essential to uncover its elusive causes and enable cascade family screening. This study aimed to enhance the identification of likely causative variants in juvenile SCD cases (age ≤ 50 years), particularly when autopsy findings are inconclusive. Autopsy revealed diagnostic structural abnormalities in 46%, non-diagnostic findings in 23%, and structurally normal hearts in 31% of cases. Whole-exome sequencing (WES), refined through a customized virtual gene panel was used to identify variants. These variants were then evaluated using a multidisciplinary approach and a structured variant prioritization scheme. Our extended approach identified likely causative variants in 69% of cases, outperforming the diagnostic yields of both the cardio panel and standard susceptibility gene analysis (50% and 16%, respectively). The extended cardio panel achieved an 80% diagnostic yield in cases with structurally normal hearts, demonstrating its efficacy in challenging scenarios. Notably, half of the positive cases harboured a single variant, while the remainder had two or more variants. This study highlights the efficacy of a multidisciplinary approach employing WES and a tailored virtual gene panel to elucidate the aetiology of juvenile SCD. The findings support the expansion of genetic testing using tailored gene panels and prioritization schemes as part of routine autopsy evaluations to improve the identification of causative variants and potentially facilitate early diagnosis in first-degree relatives.
约有 40% 的青少年心脏性猝死(SCD)病例仍然无法解释原因,这给受害者家庭和社会造成了巨大的精神负担。全面的调查对于揭示其难以捉摸的病因和实现级联家庭筛查至关重要。本研究旨在加强对青少年 SCD 病例(年龄小于 50 岁)可能致病变异的鉴定,尤其是在尸检结果不确定的情况下。尸检结果显示,46%的病例有诊断性结构异常,23%的病例无诊断性结果,31%的病例心脏结构正常。全外显子组测序(WES)通过定制的虚拟基因面板进行改进,用于识别变异。然后采用多学科方法和结构化变异优先排序方案对这些变异进行评估。我们的扩展方法在 69% 的病例中识别出了可能的致病变异体,其诊断率超过了心肌病面板和标准易感基因分析(分别为 50% 和 16%)。在心脏结构正常的病例中,扩展的心肌细胞面板的诊断率达到了80%,证明了它在具有挑战性的情况下的有效性。值得注意的是,一半的阳性病例携带一个变异体,而其余病例则携带两个或更多变异体。这项研究强调了采用 WES 和定制虚拟基因面板的多学科方法在阐明幼年 SCD 病因方面的有效性。研究结果支持在常规尸检评估中扩大使用定制基因面板和优先排序计划的基因检测范围,以改进致病变异的鉴定并促进一级亲属的早期诊断。
{"title":"Whole-exome sequencing to identify causative variants in juvenile sudden cardiac death","authors":"Martina Modena, Alberto Giannoni, Alberto Aimo, Paolo Aretini, Nicoletta Botto, Simona Vittorini, Andrea Scatena, Diana Bonuccelli, Marco Di Paolo, Michele Emdin","doi":"10.1186/s40246-024-00657-x","DOIUrl":"https://doi.org/10.1186/s40246-024-00657-x","url":null,"abstract":"Juvenile sudden cardiac death (SCD) remains unexplained in approximately 40% of cases, leading to a significant emotional burden for the victims’ families and society. Comprehensive investigations are essential to uncover its elusive causes and enable cascade family screening. This study aimed to enhance the identification of likely causative variants in juvenile SCD cases (age ≤ 50 years), particularly when autopsy findings are inconclusive. Autopsy revealed diagnostic structural abnormalities in 46%, non-diagnostic findings in 23%, and structurally normal hearts in 31% of cases. Whole-exome sequencing (WES), refined through a customized virtual gene panel was used to identify variants. These variants were then evaluated using a multidisciplinary approach and a structured variant prioritization scheme. Our extended approach identified likely causative variants in 69% of cases, outperforming the diagnostic yields of both the cardio panel and standard susceptibility gene analysis (50% and 16%, respectively). The extended cardio panel achieved an 80% diagnostic yield in cases with structurally normal hearts, demonstrating its efficacy in challenging scenarios. Notably, half of the positive cases harboured a single variant, while the remainder had two or more variants. This study highlights the efficacy of a multidisciplinary approach employing WES and a tailored virtual gene panel to elucidate the aetiology of juvenile SCD. The findings support the expansion of genetic testing using tailored gene panels and prioritization schemes as part of routine autopsy evaluations to improve the identification of causative variants and potentially facilitate early diagnosis in first-degree relatives.","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The cryptic complex rearrangements involving the DMD gene: etiologic clues about phenotypical differences revealed by optical genome mapping 涉及 DMD 基因的隐性复合重排:光学基因组图谱揭示的表型差异的病因学线索
IF 4.5 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-09-16 DOI: 10.1186/s40246-024-00653-1
Yunting Ma, Chunrong Gui, Meizhen Shi, Lilin Wei, Junfang He, Bobo Xie, Haiyang Zheng, Xiaoyun Lei, Xianda Wei, Zifeng Cheng, Xu Zhou, Shaoke Chen, Jiefeng Luo, Yan Huang, Baoheng Gui
Deletion or duplication in the DMD gene is one of the most common causes of Duchenne and Becker muscular dystrophy (DMD/BMD). However, the pathogenicity of complex rearrangements involving DMD, especially segmental duplications with unknown breakpoints, is not well understood. This study aimed to evaluate the structure, pattern, and potential impact of rearrangements involving DMD duplication. Two families with DMD segmental duplications exhibiting phenotypical differences were recruited. Optical genome mapping (OGM) was used to explore the cryptic pattern of the rearrangements. Breakpoints were validated using long-range polymerase chain reaction combined with next-generation sequencing and Sanger sequencing. A multi-copy duplication involving exons 64–79 of DMD was identified in Family A without obvious clinical symptoms. Family B exhibited typical DMD neuromuscular manifestations and presented a duplication involving exons 10–13 of DMD. The rearrangement in Family A involved complex in-cis tandem repeats shown by OGM but retained a complete copy (reading frame) of DMD inferred from breakpoint validation. A reversed insertion with a segmental repeat was identified in Family B by OGM, which was predicted to disrupt the normal structure and reading frame of DMD after confirming the breakpoints. Validating breakpoint and rearrangement pattern is crucial for the functional annotation and pathogenic classification of genomic structural variations. OGM provides valuable insights into etiological analysis of DMD/BMD and enhances our understanding for cryptic effects of complex rearrangements.
DMD 基因的缺失或重复是导致杜兴氏和贝克氏肌营养不良症(DMD/BMD)的最常见原因之一。然而,涉及 DMD 的复杂重排,尤其是断点不明的节段性重复,其致病性尚不十分清楚。本研究旨在评估涉及 DMD 重复的重排的结构、模式和潜在影响。研究人员招募了两个表现出表型差异的 DMD 节段重复家族。利用光学基因组图谱(OGM)探索重排的隐性模式。利用长程聚合酶链反应结合新一代测序和桑格测序验证了断点。在家族 A 中发现了涉及 DMD 64-79 号外显子的多拷贝重复,但无明显临床症状。家族 B 表现出典型的 DMD 神经肌肉症状,并出现涉及 DMD 第 10-13 号外显子的重复。A 家系的重排涉及 OGM 显示的复杂顺式串联重复,但保留了断点验证推断的 DMD 的完整拷贝(阅读框)。在 B 家系中,OGM 发现了一个带有片段重复的反向插入,在确认断点后,预测该插入会破坏 DMD 的正常结构和阅读框。验证断点和重排模式对于基因组结构变异的功能注释和致病性分类至关重要。OGM 为 DMD/BMD 的病因分析提供了有价值的见解,并增强了我们对复杂重排隐性效应的理解。
{"title":"The cryptic complex rearrangements involving the DMD gene: etiologic clues about phenotypical differences revealed by optical genome mapping","authors":"Yunting Ma, Chunrong Gui, Meizhen Shi, Lilin Wei, Junfang He, Bobo Xie, Haiyang Zheng, Xiaoyun Lei, Xianda Wei, Zifeng Cheng, Xu Zhou, Shaoke Chen, Jiefeng Luo, Yan Huang, Baoheng Gui","doi":"10.1186/s40246-024-00653-1","DOIUrl":"https://doi.org/10.1186/s40246-024-00653-1","url":null,"abstract":"Deletion or duplication in the DMD gene is one of the most common causes of Duchenne and Becker muscular dystrophy (DMD/BMD). However, the pathogenicity of complex rearrangements involving DMD, especially segmental duplications with unknown breakpoints, is not well understood. This study aimed to evaluate the structure, pattern, and potential impact of rearrangements involving DMD duplication. Two families with DMD segmental duplications exhibiting phenotypical differences were recruited. Optical genome mapping (OGM) was used to explore the cryptic pattern of the rearrangements. Breakpoints were validated using long-range polymerase chain reaction combined with next-generation sequencing and Sanger sequencing. A multi-copy duplication involving exons 64–79 of DMD was identified in Family A without obvious clinical symptoms. Family B exhibited typical DMD neuromuscular manifestations and presented a duplication involving exons 10–13 of DMD. The rearrangement in Family A involved complex in-cis tandem repeats shown by OGM but retained a complete copy (reading frame) of DMD inferred from breakpoint validation. A reversed insertion with a segmental repeat was identified in Family B by OGM, which was predicted to disrupt the normal structure and reading frame of DMD after confirming the breakpoints. Validating breakpoint and rearrangement pattern is crucial for the functional annotation and pathogenic classification of genomic structural variations. OGM provides valuable insights into etiological analysis of DMD/BMD and enhances our understanding for cryptic effects of complex rearrangements.","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Human Genomics
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