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Comparing the frequency of variants of uncertain significance (VUS) between ancestry groups in a paediatric epilepsy cohort. 比较儿科癫痫队列中不同祖先群体之间意义不确定变异(VUS)的频率。
IF 3.5 2区 医学 Q1 Medicine Pub Date : 2024-06-20 DOI: 10.1136/jmg-2023-109450
Bree E Martin, Tristan Sands, Louise Bier, Amanda Bergner, Amelia K Boehme, Natalie Lippa

Background: Studies indicate that variants of uncertain significance are more common in non-European populations due to lack of a diversity in population databases. This difference has not been explored in epilepsy, which is increasingly found to be genetic in paediatric populations, and has precision medicine applications. This study examines the differences in the frequency of uncertain next-generation sequencing (NGS) results among a paediatric epilepsy cohort between ancestral groups historically under-represented in biomedical research (UBR) and represented in biomedical research (RBR).

Methods: A retrospective chart review of patients with epilepsy seen at Columbia University Irving Medical Center (CUIMC). One hundred seventy-eight cases met the following criteria: (1) visited any provider within the Pediatric Neurology Clinic at CUIMC, (2) had an ICD code indicating a diagnosis of epilepsy, (3) underwent NGS testing after March 2015 and (4) had self-reported ancestry that fit into a single dichotomous category of either historically represented or under-represented in biomedical research.

Results: UBR cases had significantly higher rates of uncertain results when compared with RBR cases (79.2% UBR, 20.8% RBR; p value=0.002). This finding remained true after controlling for potential confounding factors, including sex, intellectual disability or developmental delay, epilepsy type, age of onset, number of genes tested and year of testing.

Conclusion: Our results add to the literature that individuals who are of ancestries historically under-represented in genetics research are more likely to receive uncertain genetic results than those of represented majority ancestral groups and establishes this finding in an epilepsy cohort.

背景:研究表明,由于人群数据库缺乏多样性,意义不确定的变异在非欧洲人群中更为常见。这种差异尚未在癫痫中得到探讨,而癫痫在儿科人群中越来越多地被发现具有遗传性,并具有精准医疗的应用价值。本研究探讨了历史上在生物医学研究中代表性不足的祖先群体(UBR)和在生物医学研究中有代表性的祖先群体(RBR)之间在儿科癫痫队列中不确定的下一代测序(NGS)结果频率的差异:方法:对在哥伦比亚大学欧文医学中心(CUIMC)就诊的癫痫患者进行回顾性病历审查。178例患者符合以下标准:(1)在 CUIMC 儿科神经病学门诊就诊的任何医护人员;(2)有表明癫痫诊断的 ICD 编码;(3)在 2015 年 3 月后接受 NGS 测试;(4)自报祖先符合单一二分法类别,即在生物医学研究中具有历史代表性或代表性不足:与 RBR 病例相比,UBR 病例的结果不确定率明显更高(UBR 病例为 79.2%,RBR 病例为 20.8%;P 值=0.002)。在控制了潜在的混杂因素(包括性别、智力残疾或发育迟缓、癫痫类型、发病年龄、检测基因数量和检测年份)后,这一结果依然如此:我们的研究结果补充了文献中的观点,即历史上在遗传学研究中代表性不足的祖先群体的个体比那些在遗传学研究中占多数的祖先群体的个体更有可能得到不确定的遗传结果,并在癫痫队列中证实了这一发现。
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引用次数: 0
Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis. 一大批埃利斯-范克里夫德综合征患者和一个韦氏acrofacial dysostosis家族的变异特征和临床概况。
IF 3.5 2区 医学 Q1 Medicine Pub Date : 2024-06-20 DOI: 10.1136/jmg-2023-109546
Umut Altunoglu, Adrian Palencia-Campos, Nilay Güneş, Gozde Tutku Turgut, Julian Nevado, Pablo Lapunzina, Maria Valencia, Asier Iturrate, Ghada Otaify, Rasha Elhossini, Adel Ashour, Asmaa K Amin, Rania F Elnahas, Elisa Fernandez-Nuñez, Carmen-Lisset Flores, Pedro Arias, Jair Tenorio, Carlos Israel Chamorro Fernández, Yeliz Güven, Elif Özsu, Beray Selver Eklioğlu, Marisol Ibarra-Ramirez, Birgitte Rode Diness, Birute Burnyte, Houda Ajmi, Zafer Yüksel, Ruken Yıldırım, Edip Ünal, Ebtesam Abdalla, Mona Aglan, Hulya Kayserili, Beyhan Tuysuz, Victor Ruiz-Pérez

Background: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum.

Methods: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays.

Main results: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC.

Conclusions: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

背景:埃利斯-范克里夫德综合征(Ellis-van Creveld Syndrome,简称 EvC)是一种隐性遗传疾病,主要由 EVC 或 EVC2 的致病变体引起,其特征为尖头畸形肢体短缩、轴后多指畸形、甲牙发育不良和先天性心脏缺陷。韦氏acrofacial dysostosis(WAD)是一种与EVC等位的超罕见显性遗传病。本研究旨在加强目前对 EvC 和 WAD 临床表现的了解,并扩大其突变范围:方法:我们对来自 43 个非亲缘家庭、初步临床诊断为 EvC 的 46 名患者和来自一个 WAD 家庭的 3 名患者进行了分子研究,并对临床数据进行了回顾性分析。通过细胞检测评估了某些意义不明的变异的有害影响:我们在 43 个 EvC 家族中的 41 个家族的患者体内发现了 EVC/EVC2 的致病变异。其余两个家族的患者分别发现了WDR35中的一个同源剪接变异和GLI3中的一个新发杂合框移位变异。这些患者的表型与 EvC 有明显的重叠。在 WAD 家族中发现了一种新型 EVC2 C 端截短变体。对该患者群进行的深度表型分析再现了文献中的 "经典 EvC 发现",并突出了以前未曾描述或很少描述为 EvC 一部分的发现:这项研究展示了迄今为止最大的在世 EvC 患者群,有助于更好地了解 EvC 的全部临床表现。我们还提供了有关EVC/EVC2突变情况的全面信息,并将GLI3添加到与EvC样表型相关的基因列表中。
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引用次数: 0
Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation. 新型 TUBA4A 变体会导致伴有局灶性肌纤维紊乱的先天性肌病。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-20 DOI: 10.1136/jmg-2023-109786
Yalan Wan, Chao Zhou, Xingzhi Chang, Liwen Wu, Yilei Zheng, Jiaxi Yu, Li Bai, Mingyue Luan, Meng Yu, Qi Wang, Wei Zhang, Yun Yuan, Jianwen Deng, Zhaoxia Wang

Background: Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy.

Methods: A comprehensive strategy combining laser capture microdissection, proteomics and whole-exome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of the TUBA4A variant.

Results: We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the TUBA4A (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

Conclusion: Our findings expanded the phenotypic and genetic manifestations of TUBA4A as well as tubulinopathies, and added a new type of congenital myopathy to be taken into consideration in the differential diagnosis.

背景:先天性肌病是一组在临床、组织病理学和遗传学方面具有异质性的遗传性肌肉疾病,其定义是肌纤维的特殊结构异常。虽然至少有 33 种不同的遗传病因,但仍有相当比例的先天性肌病在遗传学上未得到解决。本研究旨在报告两名无血缘关系的中国散发性先天性肌病患者的新型 TUBA4A 变异:方法:采用激光捕获显微切割、蛋白质组学和全外显子组测序相结合的综合策略来确定候选基因。此外,还回顾了现有的临床数据、肌病理学变化、电生理学检查结果和大腿肌肉核磁共振成像。我们建立了一个细胞模型来评估 TUBA4A 变异的致病性:结果:我们在两名临床病理诊断为散发性先天性肌病的非亲缘关系患者中发现了编码微管蛋白α-4A的TUBA4A(NM_006000)变异体c.679C>T(p.L227F)。这两名患者突出的肌病理学改变是肌纤维出现局灶性肌纤维紊乱和边缘空泡。免疫荧光显示,在有边缘空泡的肌纤维中,泛素阳性的TUBA4A蛋白聚集。过量表达 L227F 突变体 TUBA4A 会导致细胞质聚集,在细胞模型中与泛素共定位:我们的研究结果扩展了 TUBA4A 以及微管蛋白病的表型和遗传表现,并增加了一种新的先天性肌病类型,需要在鉴别诊断中加以考虑。
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引用次数: 0
Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases. 疾病特异性变异解读强调了 2325 名日本视网膜色素变性及相关疾病患者的遗传发现。
IF 3.5 2区 医学 Q1 Medicine Pub Date : 2024-06-20 DOI: 10.1136/jmg-2023-109750
Kensuke Goto, Yoshito Koyanagi, Masato Akiyama, Yusuke Murakami, Masatoshi Fukushima, Kohta Fujiwara, Hanae Iijima, Mitsuyo Yamaguchi, Mikiko Endo, Kazuki Hashimoto, Masataka Ishizu, Toshiaki Hirakata, Kei Mizobuchi, Masakazu Takayama, Junya Ota, Ai Fujita Sajiki, Taro Kominami, Hiroaki Ushida, Kosuke Fujita, Hiroki Kaneko, Shinji Ueno, Takaaki Hayashi, Chikashi Terao, Yoshihiro Hotta, Akira Murakami, Kazuki Kuniyoshi, Shunji Kusaka, Yuko Wada, Toshiaki Abe, Toru Nakazawa, Yasuhiro Ikeda, Yukihide Momozawa, Koh-Hei Sonoda, Koji M Nishiguchi

Background: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases.

Methods: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.

Results: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases.

Conclusion: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.

背景:随着遗传性视网膜营养不良症(IRD)基因特异性疗法的发展,各研究机构统一的变异解读变得越来越重要。本研究旨在根据美国医学遗传学和基因组学学院以及分子病理学协会的规则,应用日本 IRD 患者标准化变异解读指南(J-IRD-VI 指南),更新大量日本 RP 患者中 86 个视网膜色素变性(RP)相关基因的遗传结果,并评估这些基因在 RP 相关疾病中的贡献:我们评估了 2325 名患有 RP(n=2155,包括之前用相同测序面板测序的 n=1204)和相关疾病(n=170,新分析的)的探明者,包括乌谢尔综合征、Leber 先天性羊膜炎和锥体-杆状营养不良症(CRD)。对 86 个基因进行了目标测序。结果显示,共发现 3564 个变异基因:结果:共检测到 3564 个变异,其中 524 个变异被解释为致病或可能致病。在这 524 个变异中,有 280 个(53.4%)在我们之前对 1204 名 RP 患者的研究中未被检测到或被解释为意义不明的变异或良性变异。因此,RP 患者的基因诊断率为 38.6%,其中 EYS 患者占基因诊断患者的 46.7%,诊断率比我们之前的研究提高了 9%。CRD患者的基因诊断率为28.2%,RP相关基因的贡献率明显高于其他相关疾病:结论:利用 J-IRD-VI 指南进行的大规模基因分析突出了日本 IRD 患者的人群特异性基因发现;这些发现为基因特异性疗法的临床应用奠定了基础。
{"title":"Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases.","authors":"Kensuke Goto, Yoshito Koyanagi, Masato Akiyama, Yusuke Murakami, Masatoshi Fukushima, Kohta Fujiwara, Hanae Iijima, Mitsuyo Yamaguchi, Mikiko Endo, Kazuki Hashimoto, Masataka Ishizu, Toshiaki Hirakata, Kei Mizobuchi, Masakazu Takayama, Junya Ota, Ai Fujita Sajiki, Taro Kominami, Hiroaki Ushida, Kosuke Fujita, Hiroki Kaneko, Shinji Ueno, Takaaki Hayashi, Chikashi Terao, Yoshihiro Hotta, Akira Murakami, Kazuki Kuniyoshi, Shunji Kusaka, Yuko Wada, Toshiaki Abe, Toru Nakazawa, Yasuhiro Ikeda, Yukihide Momozawa, Koh-Hei Sonoda, Koji M Nishiguchi","doi":"10.1136/jmg-2023-109750","DOIUrl":"10.1136/jmg-2023-109750","url":null,"abstract":"<p><strong>Background: </strong>As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases.</p><p><strong>Methods: </strong>We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.</p><p><strong>Results: </strong>A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with <i>EYS</i> accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases.</p><p><strong>Conclusion: </strong>A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes. ZFHX3变体可导致儿童部分性癫痫和婴儿痉挛症,且结果良好。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-20 DOI: 10.1136/jmg-2023-109725
Ming-Feng He, Li-Hong Liu, Sheng Luo, Juan Wang, Jia-Jun Guo, Peng-Yu Wang, Qiong-Xiang Zhai, Su-Li He, Dong-Fang Zou, Xiao-Rong Liu, Bing-Mei Li, Hai-Yan Ma, Jing-Da Qiao, Peng Zhou, Na He, Yong-Hong Yi, Wei-Ping Liao

Background: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy.

Methods: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy.

Results: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth.

Conclusion: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.

背景:ZFHX3基因在胚胎发育、细胞增殖、神经元分化和神经元死亡中发挥着重要作用。本研究旨在探讨 ZFHX3 基因变异与癫痫之间的关系:方法:对378名部分性(局灶性)癫痫患者进行了全外显子组测序。采用果蝇 Zfh2 基因敲除模型验证 ZFHX3 与癫痫的关系:结果:在8例无关病例中发现了ZFHX3复合杂合变体。多重/特异性统计分析显示,病例队列中 ZFHX3 变体的负担明显较高。在 Zfh2 基因敲除的苍蝇中,癫痫样行为的发生率和持续时间明显高于对照组。Zfh2基因敲除的苍蝇表现出更多的兴奋性神经元点燃。所有患者都出现了部分性癫痫发作。C端/N端变异的五名患者表现为轻度部分性癫痫。另外三名患者中,一名经常出现非惊厥性癫痫状态,两名出现早期痉挛。这三名患者也有神经发育异常,被诊断为发育性癫痫性脑病(DEE),但在接受抗癫痫药物治疗而不使用促肾上腺皮质激素/类固醇后,癫痫不再发作。对时间表达(遗传依赖阶段)的分析表明,ZFHX3同源物在胚胎期高度表达,出生后则急剧下降:结论:ZFHX3 是儿童部分性癫痫和 DEE 的新型致病基因。结论:ZFHX3 是儿童部分性癫痫和 DEE 的新致病基因,婴儿痉挛症患者在不使用促肾上腺皮质激素/类固醇治疗后癫痫不再发作,这意味着基因诊断在精确治疗中具有重要意义。遗传依赖阶段让人们了解了疾病演变过程的内在机制。
{"title":"<i>ZFHX3</i> variants cause childhood partial epilepsy and infantile spasms with favourable outcomes.","authors":"Ming-Feng He, Li-Hong Liu, Sheng Luo, Juan Wang, Jia-Jun Guo, Peng-Yu Wang, Qiong-Xiang Zhai, Su-Li He, Dong-Fang Zou, Xiao-Rong Liu, Bing-Mei Li, Hai-Yan Ma, Jing-Da Qiao, Peng Zhou, Na He, Yong-Hong Yi, Wei-Ping Liao","doi":"10.1136/jmg-2023-109725","DOIUrl":"10.1136/jmg-2023-109725","url":null,"abstract":"<p><strong>Background: </strong>The <i>ZFHX3</i> gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between <i>ZFHX3</i> variants and epilepsy.</p><p><strong>Methods: </strong>Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A <i>Drosophila Zfh2</i> knockdown model was used to validate the association between <i>ZFHX3</i> and epilepsy.</p><p><strong>Results: </strong>Compound heterozygous <i>ZFHX3</i> variants were identified in eight unrelated cases. The burden of <i>ZFHX3</i> variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In <i>Zfh2</i> knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The <i>Zfh2</i> knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that <i>ZFHX3</i> orthologous were highly expressed in the embryonic stage and decreased dramatically after birth.</p><p><strong>Conclusion: </strong><i>ZFHX3</i> is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Extent of investigation and management of cases of 'unexplained' mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus. 不明原因 "错配修复缺陷(u-dMMR)病例的调查和管理范围:英国癌症遗传学小组共识。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-20 DOI: 10.1136/jmg-2024-109886
Terri Patricia McVeigh, Kevin J Monahan, Joseph Christopher, Nick West, Malcolm Scott, Jennie Murray, Helen Hanson

Background: Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR.

Methods: This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance.

Results: We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS.

Conclusion: Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.

背景:错配修复缺陷(dMMR)是林奇综合征相关癌症的一个特征。然而,在大多数情况下,它是由偶发性体细胞事件而非遗传因素引起的。林奇样综合征"(LLS)一词被用来指导对患有 dMMR 肿瘤的亲属进行结直肠癌监测,因为体细胞和种系基因组检测并不能提供信息。随着通过免疫组化和/或微卫星不稳定性评估错配修复的方法越来越多地应用于各种肿瘤类型的治疗规划,在遗传病因可疑度较低的肿瘤中发现 dMMR 的情况也越来越多。我们的目标是确定当前的做法,并为调查和管理显示不明原因 dMMR 的癌症患者亲属制定国家指南:方法: 我们召开了一次由英国主要利益相关者参加的虚拟共识会议,通过会前调查、结构化讨论和会中投票来制定最佳实践指南:结果:我们发现各专科中心在提供诊断技术方面存在差异。与会者一致认为,需要公平地进行基线检测,并承认需要采取务实的方法来调查传统上与林奇综合征无关的 dMMR 癌症。家族史、年龄、肿瘤类型、蛋白质丢失模式和检查范围等因素被认为是指导家庭管理的关键。建议使用 "原因不明的 dMMR "一词,而不是 LLS:结论:在决定对患者及其亲属进行检查和未来癌症风险管理时,应考虑各种因素,如临床怀疑遗传倾向等,以有效分配有限的资源,避免对低怀疑家族进行不必要的检查。
{"title":"Extent of investigation and management of cases of 'unexplained' mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus.","authors":"Terri Patricia McVeigh, Kevin J Monahan, Joseph Christopher, Nick West, Malcolm Scott, Jennie Murray, Helen Hanson","doi":"10.1136/jmg-2024-109886","DOIUrl":"10.1136/jmg-2024-109886","url":null,"abstract":"<p><strong>Background: </strong>Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR.</p><p><strong>Methods: </strong>This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance.</p><p><strong>Results: </strong>We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS.</p><p><strong>Conclusion: </strong>Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability. Plexin B2 (PLXNB2)的双叶变体会导致成骨不全症、听力损失和智力障碍。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-20 DOI: 10.1136/jmg-2023-109728
Claire E L Smith, Virginie Laugel-Haushalter, Ummey Hany, Sunayna Best, Rachel L Taylor, James A Poulter, Saskia B Wortmann, Rene G Feichtinger, Johannes A Mayr, Suhaila Al Bahlani, Georgios Nikolopoulos, Alice Rigby, Graeme C Black, Christopher M Watson, Sahar Mansour, Chris F Inglehearn, Alan J Mighell, Agnès Bloch-Zupan

Background: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease.

Methods: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice.

Results: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts.

Conclusion: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.

背景:Plexins是semaphorin家族信号蛋白的大型跨膜受体。鞘磷脂-plexin 信号控制着细胞间的相互作用,这种相互作用在发育过程中和成年阶段都至关重要。人类已发现九个plexin基因,但尽管plexin在发育过程中具有明显的重要性,迄今只有PLXND1和PLXNA1的双倍变体与孟德尔遗传病有关:来自 6 个家庭的 8 人患有隐性遗传的多变临床症状,其核心特征是成髓不全症(AI)和感音神经性听力损失(SNHL),并伴有不同程度的智力障碍。研究人员通过外显子组或基因组测序对原型进行了调查。常见变异和不太可能影响功能的变异被排除在外。符合常染色体隐性遗传的变异被优先考虑。变异分离分析通过桑格测序法进行。在 C57Bl6 小鼠中进行了 RNA 表达分析:结果:在所有六个家系中都发现了罕见的双倍拷贝致病变体 plexin B2 (PLXNB2),这是一种大型跨膜 semaphorin 受体蛋白。确定的变异包括错义、无义、剪接变化和多外显子缺失。在分化的成骨细胞中检测到了 Plxnb2 的表达:结论:我们发现 PLXNB2 的罕见双倍重复致病变体是导致以 AI 和 SNHL 为核心特征的常染色体隐性、表型多样的新型综合征的病因。智力残疾、眼部疾病、耳部发育异常和淋巴水肿也出现在多个病例中。人类多变综合征的表型与Plxnb2基因敲除小鼠的表型重叠,再加上人类PLXNB2变体的罕见性,这也许可以解释为什么以前没有报道过PLXNB2的致病变体。
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引用次数: 0
Rare variant association analyses reveal the significant contribution of carbohydrate metabolic disturbance in severe adolescent idiopathic scoliosis. 罕见变异关联分析揭示了碳水化合物代谢紊乱在严重青少年特发性脊柱侧凸中的重要作用。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-20 DOI: 10.1136/jmg-2023-109667
Wen Wen, Zhengye Zhao, Zhifa Zheng, Sen Zhao, Hengqiang Zhao, Xi Cheng, Huakang Du, Ziquan Li, Shengru Wang, Guixing Qiu, Zhihong Wu, Terry Jianguo Zhang, Nan Wu

Background: Adolescent idiopathic scoliosis (AIS), the predominant genetic-influenced scoliosis, results in spinal deformities without vertebral malformations. However, the molecular aetiology of AIS remains unclear.

Methods: Using genome/exome sequencing, we studied 368 patients with severe AIS (Cobb angle >40°) and 3794 controls from a Han Chinese cohort. We performed gene-based and pathway-based weighted rare variant association tests to assess the mutational burden of genes and established biological pathways. Differential expression analysis of muscle tissues from 14 patients with AIS and 15 controls was served for validation.

Results: SLC16A8, a lactate transporter linked to retinal glucose metabolism, was identified as a novel severe AIS-associated gene (p=3.08E-06, false discovery rate=0.009). Most AIS cases with deleterious SLC16A8 variants demonstrated early onset high myopia preceding scoliosis. Pathway-based burden test also revealed a significant enrichment in multiple carbohydrate metabolism pathways, especially galactose metabolism. Patients with deleterious variants in these genes demonstrated a significantly larger spinal curve. Genes related to catabolic processes and nutrient response showed divergent expression between AIS cases and controls, reinforcing our genomic findings.

Conclusion: This study uncovers the pivotal role of genetic variants in carbohydrate metabolism in the development of AIS, unveiling new insights into its aetiology and potential treatment.

背景:青少年特发性脊柱侧弯症(AIS)是受遗传影响最严重的脊柱侧弯症,会导致脊柱畸形而无脊椎畸形。然而,AIS 的分子病因仍不清楚:利用基因组/外显子组测序技术,我们研究了来自中国汉族队列的 368 名重度 AIS 患者(Cobb 角大于 40°)和 3794 名对照者。我们进行了基于基因和通路的加权罕见变异关联测试,以评估基因突变负担和已建立的生物通路。我们还对14名AIS患者和15名对照者的肌肉组织进行了差异表达分析,以进行验证:结果:与视网膜葡萄糖代谢有关的乳酸转运体SLC16A8被鉴定为新的严重AIS相关基因(p=3.08E-06,假发现率=0.009)。大多数有SLC16A8有害变异的AIS病例在脊柱侧弯之前都有早发性高度近视。基于通路的负荷测试还显示,多个碳水化合物代谢通路,尤其是半乳糖代谢通路,出现了显著的富集。这些基因中存在有害变异的患者脊柱曲线明显增大。与分解代谢过程和营养反应相关的基因在AIS病例和对照组之间的表达存在差异,这进一步证实了我们的基因组学发现:这项研究揭示了碳水化合物代谢中的基因变异在 AIS 发病过程中的关键作用,为其病因学和潜在治疗方法提供了新的视角。
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引用次数: 0
NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways. NASP 基因通过对神经和免疫途径的表观遗传失调导致自闭症。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-20 DOI: 10.1136/jmg-2023-109385
Sipeng Zhang, Jie Yang, Dandan Ji, Xinyi Meng, Chonggui Zhu, Gang Zheng, Joseph Glessner, Hui-Qi Qu, Yuechen Cui, Yichuan Liu, Wei Wang, Xiumei Li, Hao Zhang, Zhanjie Xiu, Yan Sun, Ling Sun, Jie Li, Hakon Hakonarson, Jin Li, Qianghua Xia

Background: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology.

Methods: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene.

Results: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene.

Conclusion: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.

背景:表观遗传学对自闭症谱系障碍(ASD)的病因学有重大贡献,可能蕴藏着预防ASD发展的独特机会。我们的目的是找出与自闭症谱系障碍病因学有关的新型表观遗传学基因:方法:我们对 ASD 家庭进行了基于三重全外显子组测序。采用基因组编辑技术在相关细胞系中敲除候选致病基因。对候选基因进行ATAC-seq、ChIP-seq和RNA-seq分析,以研究基因敲除(KO)或突变对其功能的影响:结果:我们在一个中国核心家庭中发现了一个新的候选基因NASP(核自身抗原精子蛋白),该基因可导致自闭症表观遗传失调。tNASP KO增加了染色质的可及性,促进了富含突触信号的基因启动子的活跃状态,并导致神经信号和免疫信号通路中的基因表达上调。与野生型 tNASP 相比,tNASP(Q289X) 提高了脑内富集表达基因的染色质可及性。RNA-seq显示,参与神经和免疫信号传导的基因受到了tNASP突变的影响,这与秀丽隐杆线虫中nasp-1突变的表型影响和分子效应是一致的。我们还发现另外两名 ASD 患者携带 NASP 基因缺失或有害突变:我们发现了由 tNASP 介导的新型表观遗传学机制,这种机制可能有助于 ASD 及其免疫合并症的发病机制。
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引用次数: 0
Survey of service needs to embed genome sequencing for motor neuron disease in neurology in the English National Health Service. 英国国民医疗服务机构神经内科运动神经元疾病基因组测序服务需求调查。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-20 DOI: 10.1136/jmg-2023-109735
Jade Howard, Hilary L Bekker, Christopher J McDermott, Alisdair McNeill

All people with motor neuron disease (pwMND) in England are eligible for genome sequencing (GS), with panel-based testing. With the advent of genetically targeted MND treatments, and increasing demand for GS, it is important that clinicians have the knowledge and skills to support pwMND in making informed decisions around GS. We undertook an online survey of clinical genomic knowledge and genetic counselling skills in English clinicians who see pwMND. There were 245 respondents to the survey (160 neurology clinicians and 85 genetic clinicians). Neurology clinicians reported multiple, overlapping barriers to offering pwMND GS. Lack of time to discuss GS in clinic and lack of training in genetics were reported. Neurology clinicians scored significantly less well on self-rated genomic knowledge and genetic counselling skills than genetic clinicians. The majority of neurology clinicians reported that they do not have adequate educational or patient information resources to support GS discussions. We identify low levels of genomic knowledge and skills in the neurology workforce. This may impede access to GS and precision medicine for pwMND.

在英格兰,所有运动神经元病患者(pwMND)都有资格进行基因组测序(GS),并进行基于面板的测试。随着基因靶向 MND 治疗的出现以及对 GS 需求的增加,临床医生必须具备相关知识和技能,以支持 pwMND 患者就 GS 做出知情决定。我们对接诊 pwMND 的英国临床医生的临床基因组知识和遗传咨询技能进行了在线调查。共有 245 名受访者(160 名神经病学临床医生和 85 名遗传学临床医生)参与了调查。神经科临床医生表示,在为 pwMND 提供 GS 方面存在多重障碍。据报告,临床医生没有时间讨论 GS,也缺乏遗传学方面的培训。神经科临床医生在自我评价基因组知识和遗传咨询技能方面的得分明显低于遗传科临床医生。大多数神经科临床医生表示,他们没有足够的教育或患者信息资源来支持 GS 讨论。我们发现神经病学工作者的基因组知识和技能水平较低。这可能会阻碍 pwMND 获得 GS 和精准医疗。
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引用次数: 0
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Journal of Medical Genetics
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