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Identification of a novel mutation in patients with type A insulin resistance syndrome. a型胰岛素抵抗综合征患者一个新突变的鉴定
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2022-06-03 DOI: 10.1159/000525223
Liling Zhao, Hongmei Dai, Qin Zhang, Wenmu Hu, Ping Jin

Introduction: Type A insulin resistance syndrome is a rare type of congenital insulin resistance often caused by heterozygous mutations in the insulin receptor gene (INSR). The aim of this study is to explore the clinical and genetic characteristics of three patients with type A insulin resistance syndrome from two Chinese families.

Methods: The peripheral blood samples were collected from each family members. Whole-exome sequencing were performed on three patients.

Results: Patient #1 was diagnosed with hyperinsulinemia at the age of 11 years and presented with hirsutism, acanthosis nigricans, and polycystic ovaries by 13 years. A heterozygous c.3470A > G mutation in the INSR gene was identified in patient #1. Patient #2 was a 13-year-old girl who presented with insulin resistance, polycystic ovary, and hyperandrogenemia. A novel c.3601C > G INSR mutation was identified in patient #2. Co-segregated analysis showed that the c.3601C > G mutation was also found in her father, who had hyperinsulinemia and diabetes mellitus, which was consistent with autosomal dominant inheritance. SIFT and PolyPhen-2 predicted that the c.3470A > G and c.3601C > G mutations in INSR had damaging effects.

Conclusion: Our study expands the genotypic and phenotypic spectrum of type A insulin resistance syndrome. Awareness of the clinical features coupled with INSR gene screening is key to early detection and active intervention.

引言:A型胰岛素抵抗综合征是一种罕见的先天性胰岛素抵抗,通常由胰岛素受体基因(INSR)的杂合突变引起。本研究的目的是探讨来自两个中国家庭的三名A型胰岛素抵抗综合征患者的临床和遗传特征。方法:采集每个家庭成员的外周血样本。对三名患者进行了全外显子组测序。结果:1号患者在11岁时被诊断为高胰岛素血症,13岁时出现多毛症、黑棘皮病和多囊卵巢。在1号患者中发现了INSR基因中的杂合c.3470A>G突变。2号患者是一名13岁的女孩,表现为胰岛素抵抗、多囊卵巢和高雄激素血症。在2号患者中发现了一个新的c.3601C>G INSR突变。共分离分析显示,在她的父亲身上也发现了c.3601C>G突变,他患有高胰岛素血症和糖尿病,这与常染色体显性遗传一致。SIFT和PolyPhen-2预测INSR中的c.3470A>G和c.3601C>G突变具有破坏作用。结论:我们的研究扩展了A型胰岛素抵抗综合征的基因型和表型谱。对临床特征的认识结合INSR基因筛查是早期发现和积极干预的关键。
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引用次数: 0
The mitochondrial tRNAAsp T7561C, tRNAHis C12153T and A12172G mutations may be associated with essential hypertension in a Han Chinese pedigree. 线粒体tRNAAspT7561C、tRNAHisC12153T和A12172G突变可能与原发性高血压相关
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2022-03-28 DOI: 10.1159/000524163
Haiying Fu, Jinming Sun, Xiaoyan Xu

Objectives: Mutations in mitochondrial tRNA (mt-tRNA) are the important causes for maternally inherited hypertension, however, the pathophysiology of mt-tRNA mutations in clinical expression of hypertension remains poorly understood.

Material and methods: In this study, we report the molecular features of a Han Chinese pedigree with maternally transmitted essential hypertension. The entire mitochondrial genomes are PCR amplified and sequenced, Moreover, phylogenetic analysis, haplogroup analysis, as well as pathogenicity scoring system are used to assess the potential roles for mtDNA mutations.

Results: Strikingly, among ten matrilineal relatives, three of them suffer from variable degree of hypertension at different age at onset. Sequence analysis of the complete mitochondrial genomes suggests the presence of three possible pathogenic mtDNA mutations: tRNAAsp T7561C, tRNAHis C12153T and A12172G, together with a set of variants belonging to East Asian mitochondrial haplogroup M7a. Interestingly, the T7561C mutation occurs at position 44 in the variable region of tRNAAsp, while the C12153T and A12172G mutations are localized at extremely conserved nucleotides in the D-arm and anticodon stem of tRNAHis gene, respectively, which are critical for tRNA steady-state level and function.

Conclusions: Mitochondrial T7561C, C12153T and A12172G mutations may lead to the failure in tRNAs metabolism, and cause mitochondrial dysfunction that is responsible for hypertension. However, the homoplasmy form of mt-tRNA mutations, incomplete penetrance of hypertension suggest that T7561C, C12153T and A12172G mutations are insufficient to produce the clinical phenotype, hence, other risk factors such as environmental factors, nuclear genes and epigenetic modifications may contribute to the phenotypic manifestation of maternally inherited hypertension in this Chinese pedigree.

目的:线粒体tRNA(mt-tRNA)突变是母体遗传性高血压的重要原因;然而,mt-tRNA突变在高血压临床表达中的病理生理学仍然知之甚少。材料与方法:本研究报告了一个原发性高血压母系遗传的汉族家系的分子特征。对整个线粒体基因组进行PCR扩增和测序。此外,系统发育分析、单倍群分析以及致病性评分系统用于评估mtDNA突变的潜在作用。结果:10位母系亲属中,3位在不同发病年龄段有不同程度的高血压。完整线粒体基因组的序列分析表明,存在三种可能的致病性mtDNA突变:tRNAAsp T7561C、tRNAHis C12153T和A12172G,以及一组属于东亚线粒体单倍群M7a的变体。有趣的是,T7561C突变发生在tRNAAsp可变区的44位,而C12153T和A12172G突变分别位于tRNAHis基因的D臂和反密码子茎中极其保守的核苷酸处,这对tRNA稳态水平和功能至关重要。结论:线粒体T7561C、C12153T和A12172G突变可能导致tRNA代谢失败,并导致线粒体功能障碍,这是高血压的原因。然而,mt-tRNA突变的同源性形式,高血压的不完全外显率表明T7561C、C12153T和A12172G突变不足以产生临床表型;因此,环境因素、核基因和表观遗传学修饰等其他危险因素可能有助于该中国家系母系遗传性高血压的表型表现。
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引用次数: 0
Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts. 多种族群体釉质发育不全的遗传分析。
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2022-02-16 DOI: 10.1159/000522642
Rasha N Alotaibi, Brian J Howe, Lina M Moreno Uribe, Carla Sanchez, Frederic W B Deleyiannis, Carmencita Padilla, Fernando A Poletta, Ieda M Orioli, Carmen J Buxó, George L Wehby, Alexandre R Vieira, Jeffrey Murray, Consuelo Valencia-Ramírez, Claudia P Restrepo Muñeton, Ross E Long, John R Shaffer, Steven E Reis, Seth M Weinberg, Katherine Neiswanger, Daniel W McNeil, Mary L Marazita

Enamel hypoplasia causes reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7-82 years. Mixed-models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (P < 510-8), and many suggestive association signals (510-8 < P < 510-6) near genes with plausible roles in tooth/enamel development. The strongest association signal (P = 1.5710-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.

釉质发育不全导致受影响的釉质厚度减少,是最常见的牙齿畸形之一。这种缺陷是由干扰牙齿形成的环境和/或遗传因素造成的,因此从流行病学和遗传学的角度研究釉质发育不全问题非常重要。我们在多个队列中对釉质发育不全进行了全基因组关联研究,这些队列共有 7159 人,年龄在 7-82 岁之间。研究采用混合模型检验遗传关联性,同时考虑亲缘关系和遗传群体结构。然后进行元分析。在单个队列中检测了 500 多万个单核苷酸多态性。通过对个体队列和元分析的分析,发现了接近全基因组意义的关联信号(P < 510-8),以及在牙齿/珐琅质发育中具有合理作用的基因附近的许多提示性关联信号(510-8 < P < 510-6)。最强烈的关联信号(P = 1.5710-9)出现在一个个体队列中的 BMP2K 附近。在荟萃分析中,还在对牙齿发育有合理作用的基因附近观察到了其他提示性信号,如可影响釉质发育不全的 SLC4A4。需要进行更多的人类基因研究来复制这些结果,还需要在模型系统中进行功能研究来验证我们的发现。
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引用次数: 0
50th European Mathematical Genetics Meeting (EMGM) 2022. 2022年第50届欧洲数学遗传学会议
IF 1.1 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2022-01-01 Epub Date: 2022-04-20 DOI: 10.1159/000524615
Jennifer Asimit
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引用次数: 0
Front & Back Matter 正面和背面事项
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2021-12-01 DOI: 10.1159/000521474
G. Dahlberg
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引用次数: 0
Front & Back Matter 正面和背面
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2021-07-01 DOI: 10.1159/000518555
G. Dahlberg
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引用次数: 0
Front & Back Matter 正面和背面事项
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2021-05-01 DOI: 10.1159/000517133
69 49th European Mathematical Genetics Meeting (EMGM) 2021 Génin, E. (Brest) Cover illustration © iStock.com know what matters in karger.com/genetics Genetics K I2 01 67 _g en et ic s_ 28 0 IA 21 03 6_ 21 0x 28 0 Practical e-learning on setting up genetic testing in European hospitals Can my hospital benefi t from next-generation sequencing? This free-to-access, e-learning course has been created for hospital directors and medical managers of European hospitals wishing to improve their genetic testing. It has been compiled by a multidisciplinary team of expert authors from pathology, health economics, and bioinformatics. Students will leave with a solid understanding of the benefi ts of genetic testing, and the practical implications of setting up either an in-house laboratory or outsourced analyses. Authors: Fernando Schmitt; Rhodri Saunders; Stefan Nicolet FREE ENROLLMENT!
69第49届欧洲数学遗传学会议(EMGM)2021 Génin,E.(Brest)封面插图©iStock.com know what matters in karger.com/Genetics Genetics K I2 01 67 _G en et ic s_ 28 0 IA 21 03 6_ 21 0x 28 0关于在欧洲医院进行基因检测的实用电子学习我的医院能从下一代测序中受益吗?这门免费的电子学习课程是为希望改进基因检测的欧洲医院院长和医疗经理开设的。它是由一个由病理学、健康经济学和生物信息学专家作者组成的多学科团队编写的。离开时,学生们将对基因检测的好处以及建立内部实验室或外包分析的实际意义有一个坚实的理解。作者:Fernando Schmitt;罗德里·桑德斯;Stefan Nicolet免费注册!
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引用次数: 0
Front & Back Matter 正面和背面
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2021-03-01 DOI: 10.1159/000515579
G. Dahlberg
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引用次数: 0
Identification of Influential Variants in Significant Aggregate Rare Variant Tests. 在重要的总体罕见变异测试中识别有影响的变异。
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2021-02-10 DOI: 10.1159/000513290
Rachel Z Blumhagen, David A Schwartz, Carl D Langefeld, Tasha E Fingerlin

Introduction: Studies that examine the role of rare variants in both simple and complex disease are increasingly common. Though the usual approach of testing rare variants in aggregate sets is more powerful than testing individual variants, it is of interest to identify the variants that are plausible drivers of the association. We present a novel method for prioritization of rare variants after a significant aggregate test by quantifying the influence of the variant on the aggregate test of association.

Methods: In addition to providing a measure used to rank variants, we use outlier detection methods to present the computationally efficient Rare Variant Influential Filtering Tool (RIFT) to identify a subset of variants that influence the disease association. We evaluated several outlier detection methods that vary based on the underlying variance measure: interquartile range (Tukey fences), median absolute deviation, and SD. We performed 1,000 simulations for 50 regions of size 3 kb and compared the true and false positive rates. We compared RIFT using the Inner Tukey to 2 existing methods: adaptive combination of p values (ADA) and a Bayesian hierarchical model (BeviMed). Finally, we applied this method to data from our targeted resequencing study in idiopathic pulmonary fibrosis (IPF).

Results: All outlier detection methods observed higher sensitivity to detect uncommon variants (0.001 < minor allele frequency, MAF > 0.03) compared to very rare variants (MAF <0.001). For uncommon variants, RIFT had a lower median false positive rate compared to the ADA. ADA and RIFT had significantly higher true positive rates than that observed for BeviMed. When applied to 2 regions found previously associated with IPF including 100 rare variants, we identified 6 polymorphisms with the greatest evidence for influencing the association with IPF.

Discussion: In summary, RIFT has a high true positive rate while maintaining a low false positive rate for identifying polymorphisms influencing rare variant association tests. This work provides an approach to obtain greater resolution of the rare variant signals within significant aggregate sets; this information can provide an objective measure to prioritize variants for follow-up experimental studies and insight into the biological pathways involved.

导言:研究罕见变异在简单和复杂疾病中的作用越来越常见。尽管在集合中测试罕见变异的常规方法比测试单个变异更有效,但确定哪些变异可能是关联的驱动因素仍是令人感兴趣的。我们提出了一种新方法,通过量化变异对关联性综合测试的影响,在显著的综合测试后对罕见变异进行优先排序:除了提供用于对变异体进行排序的测量方法外,我们还利用离群点检测方法提出了计算效率高的罕见变异体影响过滤工具(RIFT),以确定影响疾病关联的变异体子集。我们评估了几种离群点检测方法,这些方法根据基础方差测量而有所不同:四分位数间距(Tukey 栅栏)、中位数绝对偏差和 SD。我们对 50 个大小为 3 kb 的区域进行了 1000 次模拟,并比较了真阳性率和假阳性率。我们将使用内Tukey的RIFT与现有的两种方法进行了比较:P值自适应组合(ADA)和贝叶斯分层模型(BeviMed)。最后,我们将该方法应用于特发性肺纤维化(IPF)的靶向重测序研究数据:结果:与非常罕见的变异(MAF 讨论)相比,所有离群点检测方法对检测不常见变异(0.001 < 小等位基因频率,MAF > 0.03)的灵敏度都更高:总之,RIFT 在识别影响罕见变异关联测试的多态性时具有较高的真阳性率,同时保持较低的假阳性率。这项工作提供了一种方法,可在重要的集合中获得更高的罕见变异信号分辨率;这一信息可提供一种客观的衡量标准,用于确定后续实验研究中变异的优先次序,并深入了解相关的生物通路。
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引用次数: 0
Association of PNPLA3 I148M with Liver Disease Biomarkers in Latinos. pnpla3i148m与拉丁美洲人肝脏疾病生物标志物的关系
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2021-01-01 Epub Date: 2021-11-08 DOI: 10.1159/000520734
Jonathan D Roe, Luis A Garcia, Yann C Klimentidis, Dawn K Coletta

Introduction: Liver disease accounts for approximately 2 million deaths per year worldwide. The majority of liver diseases are due to complications of cirrhosis, viral hepatitis, and hepatocellular carcinoma. Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may indicate liver disease. Moreover, there are additional noninvasive liver fibrosis indices that help to estimate liver damage, including AST-to-ALT ratio, AST-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) score, and nonalcoholic fatty liver disease (NAFLD) fibrosis score. The aims of the present study were to (1) perform an association analysis of the patatin-like phospholipase domain containing 3 (PNPLA3) I148M (rs738409) variant with ALT, AST, and various liver fibrosis indices, and (2) determine whether there are gender-related differences in these associations.

Methods: We obtained demographic, anthropometric, and metabolic phenotypes from Latino adult participants (n = 503, 64% female, 36.4 ± 0.5 years) from the Arizona Insulin Resistance (AIR) registry. SNP genotyping of I148M was performed using the TaqMan allelic discrimination assay. We used linear regression for the association analyses of the genotypes with ALT, AST, and the various liver fibrosis indices. We included genotype, age, body mass index, and alcohol status in the linear regression model.

Results: The variant I148M was in Hardy-Weinberg equilibrium, with genotype distribution: non-risk CC 118, heterozygous CG 246, and risk GG 139. The G allele was significantly associated with increased ALT and AST levels (p = 7.8 × 10-7 and p = 9.7 × 10-6, respectively). Moreover, we showed that the G allele was significantly associated with higher APRI (p = 3.7 × 10-7) and FIB-4 score (p = 4.1 × 10-3). When we analyzed the data by gender, we observed similar significant trends for ALT, AST, and APRI (all, p < 0.01). In females, the G allele was significantly associated with increased FIB-4 score (p = 6.9 × 10-3), which was not observed in the males (p > 0.05). There was no association of the I148M variant with AST/ALT ratio nor NAFLD risk score, whether analyzed in all adults or by gender.

Discussion/conclusion: Our findings provide additional evidence of an association of PNPLA3 I148M with several liver disease biomarkers in male and female Latinos residing in the Southwest of the United States.

全世界每年约有200万人死于肝病。大多数肝病是由肝硬化、病毒性肝炎和肝细胞癌的并发症引起的。谷丙转氨酶(ALT)和天冬氨酸转氨酶(AST)水平升高可能提示肝脏疾病。此外,还有其他非侵入性肝纤维化指标有助于估计肝损伤,包括ast - alt比值、ast -血小板比值指数(APRI)、纤维化-4 (FIB-4)评分和非酒精性脂肪性肝病(NAFLD)纤维化评分。本研究的目的是:(1)对含有3 (PNPLA3) I148M (rs738409)变异的patatin-like磷脂酶结构域与ALT、AST及各种肝纤维化指标的相关性进行分析,(2)确定这些相关性是否存在性别差异。方法:我们从亚利桑那州胰岛素抵抗(AIR)登记处获得拉丁裔成年参与者(n = 503, 64%女性,36.4±0.5岁)的人口统计学、人体测量学和代谢表型。采用TaqMan等位基因鉴别法对I148M进行SNP基因分型。我们使用线性回归分析基因型与ALT、AST和各种肝纤维化指标的相关性。我们在线性回归模型中纳入了基因型、年龄、体重指数和酒精状况。结果:变异I148M符合Hardy-Weinberg平衡,基因型分布为无风险CC 118,杂合CG 246,风险GG 139。G等位基因与ALT和AST水平升高显著相关(p = 7.8 × 10-7和p = 9.7 × 10-6)。此外,我们发现G等位基因与较高的APRI (p = 3.7 × 10-7)和FIB-4评分(p = 4.1 × 10-3)显著相关。当我们按性别分析数据时,我们观察到ALT、AST和APRI类似的显著趋势(均p < 0.01)。在女性中,G等位基因与FIB-4评分升高有显著相关性(p = 6.9 × 10-3),而在男性中无显著相关性(p > 0.05)。无论是在所有成年人中还是按性别分析,I148M变异与AST/ALT比率和NAFLD风险评分均无关联。讨论/结论:我们的研究结果提供了PNPLA3 I148M与居住在美国西南部的男性和女性拉丁美洲人的几种肝脏疾病生物标志物相关的额外证据。
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引用次数: 3
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Human Heredity
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