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A Comprehensive Study of Disease-Causing Variants in PAH, QDPR, PTS, and PCD Genes in Iranian Patients with Hyperphenylalaninemia: A Systematic Review. 伊朗高苯丙氨酸血症患者中 PAH、QDPR、PTS 和 PCD 基因致病变异的综合研究:系统回顾
IF 1.1 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2023-01-01 Epub Date: 2023-01-16 DOI: 10.1159/000529037
Mahmoud Ghanei, Seyedeh Helia Sadat Fatemi, Tayebeh Hamzehlouei

Background: Hyperphenylalaninemia (HPA) is an autosomal recessive disorder that results from a deficiency in the phenylalanine hydroxylase enzyme (PAH) or from a flaw in the genes that are responsible for the biosynthesis or regeneration of the cofactor tetrahydrobiopterin (BH4), including GCH1, SR, QDPR, PTS, and PCD. Identification of disease-causing variants in these genes can help physicians and clinical geneticists in differential diagnosis, appropriate prescription drugs, and saving time and cost. This study attempted to identify these genes' most prevalent disease-causing variants in Iranian HPA patients.

Summary: This study was performed under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Before it started, the flow work and inclusion/exclusion criteria were published as a protocol in PROSPERO (CRD42021273705). We conducted a comprehensive search on December 10, 2022, on international online databases, including Web of Science, Scopus, EMBASE, Science Direct, PubMed/Medline, Google Scholar, SID, ISC, and Magiran search engine, to find pertinent publications. Some studies were chosen based on inclusion and exclusion criteria. Altogether, 1,243 Iranian patients from 13 articles were considered. In total, we identified 129 distinct disease-causing variants in PAH (20 novel variants), 29 in QDPR (17 novel variants), 15 in PTS (seven novel variants), and one novel variant in PCD. Twenty disease-causing variants for PAH, 18 for QDPR, and 8 for PTS are included in the genes' proposed genetic diagnostic panels. These panels include more than 75% of the documented disease-causing variants in the Iranian population.

Key messages: The findings of this research illustrated the spectrum of disease-causing variants in the PAH, QDPR, PTS, and PCD genes identified in Iranian HPA patients. Common disease-causing variants of these genes may be chosen as a preliminary diagnostic panel for early diagnosis and lowering therapy costs.

背景:高苯丙氨酸血症(HPA)是一种常染色体隐性遗传疾病,由苯丙氨酸羟化酶(PAH)缺乏或负责辅因子四氢生物蝶呤(BH4)的生物合成或再生的基因缺陷引起,包括 GCH1、SR、QDPR、PTS 和 PCD。鉴定这些基因中的致病变异体有助于医生和临床遗传学家进行鉴别诊断、对症下药并节省时间和成本。本研究试图确定这些基因在伊朗 HPA 患者中最普遍的致病变异。摘要:本研究根据系统综述和荟萃分析首选报告项目(PRISMA)指南进行。在研究开始之前,研究流程和纳入/排除标准已作为协议发布在 PROSPERO (CRD42021273705)上。我们于 2022 年 12 月 10 日在国际在线数据库(包括 Web of Science、Scopus、EMBASE、Science Direct、PubMed/Medline、Google Scholar、SID、ISC 和 Magiran 搜索引擎)中进行了全面搜索,以找到相关出版物。根据纳入和排除标准选择了一些研究。共考虑了 13 篇文章中的 1,243 名伊朗患者。我们总共发现了 129 个不同的 PAH 致病变异体(20 个新型变异体)、29 个 QDPR 致病变异体(17 个新型变异体)、15 个 PTS 致病变异体(7 个新型变异体)和 1 个 PCD 致病变异体。PAH 的 20 个致病变异体、QDPR 的 18 个致病变异体和 PTS 的 8 个致病变异体已被纳入基因的拟议基因诊断面板中。这些基因组包括了伊朗人口中超过 75% 已记录的致病变体:本研究结果说明了在伊朗 HPA 患者中发现的 PAH、QDPR、PTS 和 PCD 基因致病变异的范围。可选择这些基因中的常见致病变异作为初步诊断面板,以进行早期诊断并降低治疗成本。
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引用次数: 0
Violation of the constant genetic effect assumption can result in biased estimates for non-linear Mendelian randomization 违反恒定遗传效应假设可能导致对非线性孟德尔随机化的有偏估计
IF 1.8 4区 生物学 Q4 GENETICS & HEREDITY Pub Date : 2022-10-31 DOI: 10.1101/2022.10.26.22280570
S. Burgess
Non-linear Mendelian randomization is an extension of conventional Mendelian randomization that performs separate instrumental variable analyses in strata of the study population with different average levels of the exposure. The approach estimates a localized average causal effect function, representing the average causal effect of the exposure on the outcome at different levels of the exposure. The commonly-used residual method for dividing the population into strata works under the assumption that the effect of the genetic instrument on the exposure is linear and constant in the study population. However, this assumption may not hold in practice. We use the recently developed doubly-ranked method to re-analyse various datasets previously analysed using the residual method. In particular, we consider a genetic score for 25-hydroxyvitamin D [25(OH)D] used in a recent non-linear Mendelian randomization analysis to assess the potential effect of vitamin D supplementation on all-cause mortality. We show that the effect of the genetic score on 25(OH)D concentrations varies strongly, with a five-fold difference in the estimated genetic association with the exposure in the lowest and highest decile groups. Evidence for a protective causal effect of vitamin D supplementation on all-cause mortality in low vitamin D individuals is evident for the residual method, but not for the doubly-ranked method. We show that the constant genetic effect assumption is more reasonable for some exposures, and less reasonable for others. If the doubly-ranked method indicates that this assumption is violated, then estimates from both the residual and doubly-ranked methods can be biased, although bias was smaller on average in the doubly-ranked method. Analysts should compare results from both methods, as well as considering transforming the exposure to reduce heterogeneity in the genetic effect on the exposure.
非线性孟德尔随机化是传统孟德尔随机化的扩展,在具有不同平均暴露水平的研究人群的阶层中进行单独的工具变量分析。该方法估计了局部平均因果效应函数,表示不同暴露水平下暴露对结果的平均因果效应。将人群划分为阶层的常用残差方法是在假设遗传工具对研究人群暴露的影响是线性和恒定的情况下工作的。然而,这一假设在实践中可能并不成立。我们使用最近开发的双重排序方法来重新分析以前使用残差方法分析的各种数据集。特别是,我们考虑了最近一项非线性孟德尔随机化分析中使用的25-羟基维生素D[25(OH)D]的遗传评分,以评估补充维生素D对全因死亡率的潜在影响。我们发现,遗传评分对25(OH)D浓度的影响变化很大,在最低和最高十分位数组中,估计的遗传关联与暴露量相差五倍。维生素D补充对低维生素D人群全因死亡率的保护性因果效应的证据在残差法中是明显的,但在双重排序法中则不然。我们表明,恒定遗传效应假设对某些暴露更合理,而对其他暴露则不太合理。如果双重排序方法表明违反了这一假设,那么残差和双重排序方法的估计都可能有偏差,尽管双重排序方法中的偏差平均较小。分析人员应比较两种方法的结果,并考虑改变暴露,以减少遗传效应对暴露的异质性。
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引用次数: 9
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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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
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Human Heredity
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