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Clinical and mutational signatures of CRB1-associated retinopathies: a multicentre study. CRB1相关视网膜病变的临床和突变特征:一项多中心研究。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-21 DOI: 10.1136/jmg-2024-110289
Mo-Ying Wang, Feng-Juan Gao, Yu-Qiao Ju, Lin-Ying Guo, Cong Duan, Qing Chang, Ting Zhang, Ge-Zhi Xu, Hui Du, Yuan Zong, Xin Huang

Background: To delineate the clinical and mutational signatures of patients with CRB1-associated retinopathies.

Methods: This multicentre retrospective cohort study involved 40 patients with CRB1 mutations and 40 age-matched and gender-matched inherited retinal diseases (IRDs). The detailed phenotyping and genotyping characteristics and genotype‒phenotype correlations of the patients were analysed.

Results: The mean age of CRB1 cohort was 27.33±14.63 years. Results showed that yellowish geographic macular degeneration (66.67%), small white or yellow dots (65.6%), hyperopia (62.5%), abnormally laminated retina (61.61%), epiretinal membrane (60.6%) and nummular pigment deposits (50%) were the most common signatures in patients with CRB1 mutations. These clinical signatures were notably more prevalent among CRB1 patients than among individuals in other IRD groups (p<0.001). Early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA) patients are more likely to present these signatures than retinitis pigmentosa (RP) and macular dystrophy (MD) patients. Furthermore, a significant reduction in central foveal thickness coupled with pronounced thickening of the peripheral retina was observed more distinctly in patients with EOSRD/LCA (p<0.001). The choroidal thickness was not significantly altered compared to the normal controls, but was markedly reduced in the other IRD groups (p<0.001). 55 pathogenic variants were identified, 20 of which were novel. Null mutations were associated with EOSRD/LCA patients, and missense mutations were more prevalent in MD and RP patients.

Conclusions: Key clinical and mutational signatures were demonstrated in this study, providing a comprehensive update on CRB1-associated retinopathies that will aid in diagnosis and lay the foundation for future therapeutic studies.

背景:研究CRB1相关视网膜病变患者的临床和突变特征:方法:这项多中心回顾性队列研究涉及 40 名 CRB1 基因突变患者和 40 名年龄和性别匹配的遗传性视网膜疾病(IRD)患者:这项多中心回顾性队列研究涉及40名CRB1突变患者和40名年龄和性别匹配的遗传性视网膜疾病(IRD)患者。研究分析了患者的详细表型和基因分型特征以及基因型与表型之间的相关性:结果:CRB1组群的平均年龄为(27.33±14.63)岁。结果显示,黄斑变性(66.67%)、小白点或黄点(65.6%)、远视(62.5%)、视网膜异常层(61.61%)、视网膜外膜(60.6%)和麻木性色素沉积(50%)是CRB1基因突变患者最常见的临床特征。这些临床特征在 CRB1 患者中的发病率明显高于其他 IRD 组别患者(结论:本研究显示了关键的临床和突变特征,为 CRB1 相关视网膜病变提供了全面的最新信息,有助于诊断并为未来的治疗研究奠定基础。
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引用次数: 0
Enhancing variant of uncertain significance (VUS) interpretation in neurogenetics: collaborative experiences from a tertiary care centre. 加强神经遗传学中意义不确定变体 (VUS) 的解释:一家三级医疗中心的合作经验。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-15 DOI: 10.1136/jmg-2024-110122
Kayla Horowitz, Nellie H Fotopoulos, Alana J Mistry, Justin Simo, Miranda Medeiros, Isabela D Bucco, Mia Ginsberg, Emily Dwosh, Roberta La Piana, Guy A Rouleau, Allison A Dilliott, Sali M K Farhan

Background: The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics patient population.

Methods: VUS Rounds brought together genetic counsellors, molecular geneticists and scientists to evaluate VUS against genomic and phenotypic evidence and assign an internal temperature classification of 'VUS Hot', 'True VUS' or 'VUS Cold', corresponding to potential pathogenicity. Biweekly meetings were held among the committee to deliberate variant classifications, determine additional clinical management actions and discuss nuances of VUS result communication.

Results: In total, 143 VUS identified in 72 individuals with neurological disease were curated between October 2022 and December 2023. Of these, 12.6% were classified as VUS Hot, carried by 22.2% of the individuals, allowing for prioritisation of additional evaluation to determine potential pathogenicity of the variants, such as clinical follow-up or segregation analysis. In contrast, 45.4% of VUS were Cold and could be eliminated from further consideration in the carrier's care. We thoroughly evaluated the various evidence that contributed to our VUS classifications and resulting clinical actions.

Conclusions: The assessment of VUS leveraging multidisciplinary collaboration allowed us to delineate required follow-up analyses for our neurology patient population. Integration of VUS Rounds into healthcare practices ensures equitable knowledge dissemination among HCPs and effective incorporation of uncertain genetic results into patient care.

背景:临床基因检测报告中发现的意义不确定变异(VUS)给医护人员(HCP)的患者护理工作带来了挑战。在此,我们介绍了在神经系统疾病三级医疗中心开展的多学科 VUS Rounds 的成果,该成果有助于解释和交流在神经遗传学患者群体中发现的 VUS:VUS Rounds汇集了遗传咨询师、分子遗传学家和科学家,他们根据基因组和表型证据对VUS进行评估,并根据潜在致病性将VUS分为 "热VUS"、"真VUS "或 "冷VUS"。委员会每两周召开一次会议,审议变异分类,确定其他临床管理措施,并讨论 VUS 结果交流的细微差别:2022 年 10 月至 2023 年 12 月期间,共对 72 名神经系统疾病患者中发现的 143 个 VUS 进行了策划。其中,12.6%被归类为VUS Hot,由22.2%的个体携带,可优先进行额外评估,以确定变异的潜在致病性,如临床随访或分离分析。与此相反,45.4% 的 VUS 为冷变异,在对携带者的治疗中可不予考虑。我们全面评估了有助于我们进行 VUS 分类和临床行动的各种证据:结论:通过多学科合作对 VUS 进行评估,我们能够为神经内科患者群体确定所需的后续分析。将 VUS Rounds 纳入医疗实践可确保在 HCPs 中公平传播知识,并将不确定的基因结果有效纳入患者护理中。
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引用次数: 0
Long-read sequencing for detection and subtyping of Prader-Willi and Angelman syndromes. 用于检测普拉德-威利综合征和安杰尔曼综合征并对其进行亚型分类的长线程测序。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-13 DOI: 10.1136/jmg-2024-110115
Vahid Akbari, Sarah Dada, Yaoqing Shen, Katherine Dixon, Duha Hejla, Andrew Galbraith, Sanaa Choufani, Rosanna Weksberg, Cornelius F Boerkoel, Laura Stewart, William T Gibson, Steven J M Jones

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinting disorders caused by genetic or epigenetic aberrations of 15q11.2-q13. Their clinical testing is often multitiered; diagnostic testing begins with methylation-specific multiplex ligation-dependent probe amplification or methylation-sensitive PCR and then proceeds to molecular subtyping to determine the mechanism and recurrence risk. Currently, correct classification of a proband's PWS/AS subtype often requires parental samples, a costly process for families and health systems. The use of nanopore sequencing for molecular diagnosis of PWS and AS has been explored by Yamada et al; however, to confirm heterodisomy parental data were still required. Here, we investigate genome-wide nanopore sequencing in a larger cohort of PWS (18) and AS (6) as a singular test to detect the molecular subtype, without parental data. We accurately subtyped these cases including uniparental heterodisomy, mixed iso-/heterodisomy, type 1 and 2 deletions, microdeletion and UBE3A indels. One PWS case with a previously unresolved diagnosis subtyped as maternal isodisomy. This work highlights the application of long-read sequencing and other imprinted regions outside of the PWS/AS critical region to resolve the molecular diagnosis and subtyping of PWS and AS without parental data. The work also outlines an approach to generically detect heterodisomy through the interrogation of distant imprinted regions.

普拉德-威利综合征(Prader-Willi syndrome,PWS)和安杰尔曼综合征(Angelman syndrome,AS)是由 15q11.2-q13 遗传或表观遗传畸变引起的印记病。它们的临床检测通常是多层次的;诊断检测从甲基化特异性多重连接依赖探针扩增或甲基化敏感 PCR 开始,然后进行分子亚型鉴定,以确定发病机制和复发风险。目前,要正确划分出疑似患者的 PWS/AS 亚型往往需要父母样本,这对家庭和医疗系统来说都是一个昂贵的过程。Yamada等人已经探索了使用纳米孔测序对PWS和AS进行分子诊断;然而,要确认异位二体仍需要父母的数据。在此,我们在一个更大的PWS(18例)和AS(6例)队列中研究了全基因组纳米孔测序,将其作为检测分子亚型的单一检测方法,而无需父母数据。我们对这些病例进行了准确的亚型分类,包括单亲异位、混合异位/异位、1 型和 2 型缺失、微缺失和 UBE3A indels。一个之前诊断未明的 PWS 病例亚型为母体异位。这项工作强调了长读数测序和 PWS/AS 临界区以外的其他印记区的应用,以便在没有父母数据的情况下解决 PWS 和 AS 的分子诊断和亚型鉴定问题。该研究还概述了一种通过询问远端印记区来检测异位二体的方法。
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引用次数: 0
Heterozygous de novo variants in HSPD1 cause hypomyelinating leukodystrophy through impaired HSP60 oligomerisation. HSPD1的杂合子从头变异体通过损害HSP60的寡聚作用导致骨髓营养不良性白质营养不良症。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-05 DOI: 10.1136/jmg-2024-109862
Marina Eskin-Schwartz, Shaikah Seraidy, Eyal Paz, Maism Molhem, Emmanuelle Ranza, Stylianos E Antonarakis, Xavier Blanc, Kristin Herman, William S Benko, Stephanie Libzon, Liat Ben Sira, Aviva Fattal-Valevski, Vadim Dolgin, Ohad S Birk, Amit Kessel, Peter Bross, Celeste Weiss, Abdussalam Azem, Ayelet Zerem

Introduction: Hypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity and ataxia. HSPD1 encodes the HSP60 chaperonin protein, mediating ATP-dependent folding of imported proteins in the mitochondrial matrix. Pathogenic variants in HSPD1 have been related to a number of neurological phenotypes, including the dominantly inherited pure hereditary spastic paraplegia (MIM 605280) and the recessively inherited hypomyelinating leukodystrophy 4 (MIM 612233). Subsequently, an additional phenotype of hypomyelinating leukodystrophy has been reported due to de novo heterozygous HSPD1 variants.In the current work, we expand the clinical and genetic spectrum of this hypomyelinating disorder by describing a cohort of three patients, being heterozygous for HSPD1 variants involving residue Ala536 of HSP60 (the novel p.Ala536Pro variant and the previously reported p.Ala536Val).

Methods: Clinical and radiological evaluation; whole exome sequencing, in vitro reconstitution assay and patient fibroblast cell lysate analysis.

Results: Clinical manifestation was of early-onset nystagmus, tremor and hypotonia evolving into spasticity and ataxia and childhood-onset neuroregression in one case. Brain MRI studies revealed diffuse hypomyelination.The 3D protein structure showed these variants to lie in spatial proximity to the previously reported Leu47Val variant, associated with a similar clinical phenotype. In vitro reconstitution assay and patient fibroblast cell lysate analysis demonstrated that these mutants display aberrant chaperonin protein complex assembly.

Discussion: We provide evidence that impaired oligomerisation of the chaperonin complex might underlie this HSPD1-related phenotype, possibly through exerting a dominant negative effect.

导言髓鞘膜下白质营养不良症是一组遗传性疾病,以严重的永久性髓鞘缺乏为特征。其临床特征包括发育迟缓,伴有或不伴有神经退化、眼球震颤、中枢性肌张力低下,并逐渐发展为痉挛和共济失调。HSPD1 编码 HSP60 合子蛋白,介导线粒体基质中进口蛋白质的 ATP 依赖性折叠。HSPD1 的致病变体与多种神经系统表型有关,包括显性遗传的纯合子遗传性痉挛性截瘫(MIM 605280)和隐性遗传的髓鞘下白质营养不良症 4(MIM 612233)。在目前的研究中,我们描述了一组由三名患者组成的队列,他们都是涉及 HSP60 残基 Ala536 的 HSPD1 变异体(新的 p.Ala536Pro 变异体和之前报道的 p.Ala536Val),从而扩展了这种骨髓营养不良性疾病的临床和遗传谱:临床和放射学评估、全外显子组测序、体外重组试验和患者成纤维细胞裂解物分析:结果:临床表现为早发性眼球震颤、震颤和肌张力低下,并逐渐发展为痉挛和共济失调,其中一例患者为儿童期神经退化。三维蛋白质结构显示,这些变异体与之前报道的Leu47Val变异体在空间上非常接近,且具有相似的临床表型。体外重组测定和患者成纤维细胞裂解物分析表明,这些突变体显示出伴侣蛋白复合物组装异常:讨论:我们提供的证据表明,合子蛋白复合物的低聚作用受损可能是 HSPD1 相关表型的基础,可能是通过发挥显性负效应造成的。
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引用次数: 0
A novel pathogenic germline chromosome 3 inversion in von Hippel-Lindau disease. von Hippel-Lindau 病的新型致病基因 3 号染色体倒位。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-23 DOI: 10.1136/jmg-2024-110202
Cathy D Vocke, Christopher J Ricketts, Svetlana Pack, Mark Raffeld, Stephen Hewitt, Alexandra P Lebensohn, Lidenys O'Brien, Rabindra Gautam, Krista Reynolds, Laura S Schmidt, Kristin Choo, Alex Kenigsberg, Sandeep Gurram, Emily Y Chew, Naris Nilubol, Prashant Chittaboina, Maria J Merino, Mark W Ball, W Marston Linehan

von Hippel-Lindau (VHL) is an autosomal-dominant hereditary tumour susceptibility disease associated with pathogenic germline variants in the VHL tumour suppressor gene. VHL patients are at increased risk of developing multiple benign and malignant tumours. Current CLIA-based genetic tests demonstrate a very high detection rate of germline VHL variants in patients with clinical manifestations of VHL. In this report, we describe a large family with canonical VHL manifestations, for which no germline alteration had been detected by conventional germline testing. We identified a novel 291 kb chromosomal inversion involving chromosome 3p in affected family members. This inversion disrupts the VHL gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family.

von Hippel-Lindau(VHL)是一种常染色体显性遗传性肿瘤易感病,与 VHL 肿瘤抑制基因的致病性种系变异有关。VHL 患者罹患多种良性和恶性肿瘤的风险增加。目前基于 CLIA 的基因检测显示,在有 VHL 临床表现的患者中,种系 VHL 变异的检出率非常高。在本报告中,我们描述了一个具有典型 VHL 表现的大家庭,传统的种系检测并未发现其种系变异。我们在受影响的家族成员中发现了一个涉及 3p 染色体的新型 291 kb 染色体倒位。这种倒位破坏了外显子 2 和外显子 3 之间的 VHL 基因,从而导致了在该家族中观察到的疾病。
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引用次数: 0
Christianson syndrome across the lifespan: genetic mutations and longitudinal study in children, adolescents, and adults. 克里斯琴森综合征:儿童、青少年和成人的基因突变和纵向研究。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-23 DOI: 10.1136/jmg-2024-109973
Brian C Kavanaugh, Jennifer Elacio, Carrie R Best, Danielle G St Pierre, Matthew F Pescosolido, Qing Ouyang, John Biedermann, Rebecca S Bradley, Judy S Liu, Richard N Jones, Eric M Morrow

Objectives: Mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome (CS). Here, in the largest study to date, we examine genetic diversity and clinical progression in CS into adulthood.

Method: Data were collected as part of the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study. 44 individuals with 31 unique NHE6 mutations, age 2-32 years, were followed prospectively, herein reporting baseline, 1 year follow-up and retrospective natural history.

Results: We present data on the CS phenotype with regard to physical growth and adaptive and motor regression across the lifespan including information on mortality. Longitudinal data on body weight and height were examined using a linear mixed model. The rate of growth across development was slow and resulted in prominently decreased age-normed height and weight by adulthood. Adaptive functioning was longitudinally examined; a majority of adult participants (18+ years) lost gross and fine motor skills over a 1 year follow-up. Previously defined core diagnostic criteria for CS (present in>85%)-namely non-verbal status, intellectual disability, epilepsy, postnatal microcephaly, ataxia, hyperkinesia-were universally present in age 6-16; however, an additional core feature of high pain tolerance was added (present in 91%). While neurologic examinations were consistent with cerebellar dysfunction, importantly, a majority of individuals (>50% older than 10) also had corticospinal tract abnormalities. Three participants died during the period of the study.

Conclusions: In this large and longitudinal study of CS, we begin to define the trajectory of symptoms and the adult phenotype thereby identifying critical targets for treatment.

目的:X连锁内体Na+/H+交换子6(NHE6)突变会导致克里斯蒂安森综合征(CS)。在这项迄今为止规模最大的研究中,我们研究了CS的遗传多样性和成年后的临床进展:数据收集是国际克里斯琴森综合征和 NHE6(SLC9A6)基因网络研究的一部分。我们对年龄在 2-32 岁、具有 31 种独特 NHE6 基因突变的 44 名患者进行了前瞻性随访,在此报告基线、1 年随访和回顾性自然病史:结果:我们提供了关于 CS 表型的数据,涉及整个生命周期的身体发育、适应性和运动退行,包括死亡率信息。我们使用线性混合模型对体重和身高的纵向数据进行了研究。在整个发育过程中,生长速度缓慢,导致成年后年龄标准身高和体重显著下降。对适应功能进行了纵向研究;大多数成年参与者(18 岁以上)在一年的随访中丧失了粗大运动和精细运动技能。以前定义的 CS 核心诊断标准(85% 以上存在)--即非语言状态、智力障碍、癫痫、产后小头畸形、共济失调、运动机能亢进--在 6-16 岁时普遍存在;但是,又增加了一个核心特征,即高疼痛耐受性(91% 存在)。虽然神经系统检查与小脑功能障碍一致,但重要的是,大多数患者(超过 50% 年龄大于 10 岁)还存在皮质脊髓束异常。研究期间,有三名参与者死亡:在这项关于 CS 的大型纵向研究中,我们开始确定症状的发展轨迹和成人表型,从而确定关键的治疗目标。
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引用次数: 0
Novel variants and genotype-phenotype correlation in a multicentre cohort of GNE myopathy in China. 中国GNE肌病多中心队列中的新变异及基因型与表型的相关性。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-23 DOI: 10.1136/jmg-2024-110149
Kexin Jiao, Jialong Zhang, Qiuxiang Li, Xiaoqing Lv, Yanyan Yu, Bochen Zhu, Huahua Zhong, Xu'en Yu, Jia Song, Qing Ke, Fangyuan Qian, Xinghua Luan, Xiaojie Zhang, Xueli Chang, Liang Wang, Meirong Liu, Jihong Dong, Zhangyu Zou, Bitao Bu, Haishan Jiang, LingChun Liu, Yue Li, Dongyue Yue, Xuechun Chang, Yongsheng Zheng, Ningning Wang, Mingshi Gao, Xingyu Xia, Nachuan Cheng, Tao Wang, Su-Shan Luo, Jianying Xi, Jie Lin, Jiahong Lu, Chongbo Zhao, Huan Yang, Pengfei Lin, Daojun Hong, Zhe Zhao, Zhiqiang Wang, Wenhua Zhu

Background: GlcNAc2-epimerase (GNE) myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway.

Objective: This multi-centre study aimed to delineate the clinical phenotype and GNE variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations.

Methods: We retrospectively analysed GNE variants from 113 patients, integrating these data with external GNE variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity.

Results: This study revealed 97 distinct GNE variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic GNE variant, c.620A>T, might underlie the milder phenotype of Chinese patients.

Conclusions: Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of GNE variants. Patients with the non-catalytic GNE variant, c.620A>T, had a milder disease progression and later wheelchair use.

背景:GlcNAc2-epimerase(GNE)肌病是一种罕见的常染色体隐性遗传疾病,由GNE基因中的致病变体引起,该基因在硅酸生物合成途径中起着至关重要的作用:这项多中心研究旨在描述中国患者的临床表型和 GNE 变异谱,从而加深我们对不同人群遗传多样性和临床表现的理解:我们回顾性地分析了113名患者的GNE变异体,并将这些数据与在线数据库中的外部GNE变异体进行整合,从全球视角研究其后果、分布、种族和严重程度:这项研究发现了 97 个不同的 GNE 变异,其中包括 35 个(36.08%)新型变异。研究还发现了另外两名患者的深度内含子变异 c.862+870C>T,而全基因组测序(WGS)发现了另外两个新型内含子变异:c.52-8924G>T 和 c.1505-12G>A。Nanopore 长读数测序(LRS)和进一步的 PCR 分析验证了 chr9:36249241 处的 639 bp 插入。错义变体主要位于表酶/激酶结构域编码区,表明催化功能受损是关键的致病后果。与日本人、韩国人和犹太人的比较研究显示,我们的队列发病年龄晚了两岁。非催化GNE变体c.620A>T的等位基因频率较高,可能是中国患者表型较轻的原因:结论:WGS 和 Nanopore LRS 等综合技术有助于鉴定 GNE 变异。具有c.620A>T非催化GNE变体的患者病情发展较轻,且较晚使用轮椅。
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引用次数: 0
Pathogenic SATB2 missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes. 影响 p.Gly392 的致病性 SATB2 错义变体具有不同的功能影响,并导致不同的临床表型。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-23 DOI: 10.1136/jmg-2024-110015
Joery den Hoed, Hirokazu Hashimoto, Mubeen Khan, Fleur Semmekrot, Katherine A Bosanko, Chihiro Abe-Hatano, Eiji Nakagawa, Hanka Venselaar, Nada Quercia, Lauren Chad, Hiroshi Kurosaka, Stephane Rondeau, Simon E Fisher, Shinya Yamamoto, Yuri A Zarate

SATB2-associated syndrome (SAS) is caused by pathogenic variants in SATB2, which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with SATB2 variants that affect p.Gly392 (four women, age range 2-16 years; p.Gly392Arg, p.Gly392Glu and p.Gly392Val). Of these, individuals with p.Gly392Arg substitutions were found to have more severe neurodevelopmental phenotypes based on an established rubric scoring system when compared with individuals with p.Gly392Glu, p.Gly392Val and other previously reported causative SATB2 missense variants. Consistent with the observations at the phenotypic level, using human cell-based and model organism functional data, we documented that while all three described p.Gly392 variants affect the same residue and seem to all have a partial loss-of-function effect, some effects on SATB2 protein function appear to be variant-specific. Our results indicate that genotype-phenotype correlations in SAS are more complex than originally thought, and variant-specific genotype-phenotype correlations are needed.

SATB2 相关综合征(SAS)是由 SATB2 的致病变异引起的,SATB2 编码一种进化保守的转录因子。在本研究中,我们描述了八名患有 SATB2 变体 p.Gly392(四名女性,年龄在 2-16 岁之间;p.Gly392Arg、p.Gly392Glu 和 p.Gly392Val)的患者。其中,与 p.Gly392Glu、p.Gly392Val 和之前报道的其他致病 SATB2 错义变异相比,根据已建立的评分系统,p.Gly392Arg 替换的个体具有更严重的神经发育表型。与表型水平的观察结果一致,我们利用基于人类细胞和模式生物体的功能数据记录发现,虽然所有三个描述的 p.Gly392 变体都影响相同的残基,而且似乎都有部分功能缺失效应,但对 SATB2 蛋白功能的某些影响似乎是变体特异性的。我们的研究结果表明,SAS 的基因型与表型之间的相关性比最初想象的要复杂得多,因此需要进行变异特异性基因型与表型之间的相关性研究。
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引用次数: 0
Genetic findings in people with schwannomas who do not meet clinical diagnostic criteria for NF2-related schwannomatosis. 不符合 NF2 相关分裂瘤病临床诊断标准的分裂瘤患者的遗传学发现。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-23 DOI: 10.1136/jmg-2024-110217
Miriam J Smith, Cristina Perez-Becerril, Mwee van der Meer, George J Burghel, Sarah J Waller, Megan Carney, Sancha Bunstone, Katherine Fryer, Naomi L Bowers, Claire L Hartley, Philip T Smith, Scott A Rutherford, Simon R Freeman, Simon K W Lloyd, Omar N Pathmanaban, Andrew Thomas King, Dorothy Halliday, Chris Duff, D Gareth Evans

Background: Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly NF2-related schwannomatosis (SWN), but when BVS are absent, this can also indicate SMARCB1-related or LZTR1-related SWN.

Methods: We assessed the variant detection rates for the three major SWN genes (NF2, LZTR1 and SMARCB1) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for NF2-related SWN at the time of genetic testing.

Results: We found that 17 (11%) people from 13 families had a germline SMARCB1 variant and 19 (12%) unrelated individuals had a germline LZTR1 variant. 19 people had an NF2 variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS).

Conclusions: There were similar proportions of LZTR1, SMARCB1 or mosaic NF2. However, since an NF2 variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification.

背景:大多数精神分裂瘤是发生在健康人身上的孤立肿瘤。但是,双侧前庭分裂瘤(BVS)或多发性非前庭分裂瘤表明存在潜在的遗传倾向。这种情况最常见的是与 NF2 相关的分裂瘤病,但如果没有前庭分裂瘤,也可能表明与 SMARCB1 相关或与 LZTR1 相关的分裂瘤病:我们评估了来自 150 个家庭的 154 人中三个主要 SWN 基因(NF2、LZTR1 和 SMARCB1)的变异检出率,这些人至少患有一个非前庭分裂瘤,但在进行基因检测时不符合 NF2 相关 SWN 的临床标准:我们发现,来自 13 个家庭的 17 人(11%)有 SMARCB1 种系变异,19 个(12%)无亲属关系的人有 LZTR1 种系变异。19人有NF2变异体,但其中18人是镶嵌的,17人只有在有两个肿瘤可供检测时才被检测出来。仅使用血液检测的总体检出率为25%,但如果将肿瘤分析包括在内,检出率则增至36%。另有12人的种系变异意义不确定(VUS):结论:LZTR1、SMARCB1 或镶嵌型 NF2 的比例相似。结论:LZTR1、SMARCB1 或镶嵌型 NF2 的比例相似。不过,由于在 103 人的肿瘤中检测到了 NF2 变异,如果有更多人的肿瘤可供分析,很可能会检测到更多镶嵌型病例。此外,如果有进一步的证据表明 VUS 具有致病性,这将大大增加基因诊断的人数比例。我们的研究结果表明了全面基因检测和改进变异分类的重要性。
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引用次数: 0
Histone modifications in Duchenne muscular dystrophy: pathogenesis insights and therapeutic implications. 杜兴氏肌肉萎缩症的组蛋白修饰:发病机理和治疗意义。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-23 DOI: 10.1136/jmg-2024-110045
Yanning Wei, Yuanyuan Jiang, Yufei Lu, Qiping Hu

Duchenne muscular dystrophy (DMD) is a commonly encountered genetic ailment marked by loss-of-function mutations in the Dystrophin gene, ultimately resulting in progressive debilitation of skeletal muscle. The investigation into the pathogenesis of DMD has increasingly converged on the role of histone modifications within the broader context of epigenetic regulation. These modifications, including histone acetylation, methylation and phosphorylation, are catalysed by specific enzymes and play a critical role in gene expression. This article provides an overview of the histone modifications occurring in DMD and analyses the research progress and potential of different types of histone modifications in DMD due to changes in cellular signalling for muscle regeneration, to provide new insights into diagnostic and therapeutic options for DMD.

杜兴氏肌肉萎缩症(DMD)是一种常见的遗传性疾病,其特点是Dystrophin基因功能缺失突变,最终导致骨骼肌进行性衰弱。对 DMD 发病机制的研究越来越多地集中在组蛋白修饰在更广泛的表观遗传调控中的作用上。这些修饰包括组蛋白乙酰化、甲基化和磷酸化,由特定的酶催化,在基因表达中起着至关重要的作用。本文概述了发生在 DMD 中的组蛋白修饰,分析了不同类型的组蛋白修饰在 DMD 中的研究进展和潜力,这些修饰是由于肌肉再生的细胞信号发生变化所致,从而为 DMD 的诊断和治疗方案提供新的见解。
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引用次数: 0
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Journal of Medical Genetics
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