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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
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 : 2024-11-04 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 group (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
Six at Sixty. Malignant peripheral nerve sheath tumours in NF1: 20-year review of a highly cited paper. 六十岁的六人。NF1恶性周围神经鞘瘤:一篇高被引论文的20年回顾。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-04 DOI: 10.1136/jmg-2024-110396
D Gareth Evans, Emma Burkitt-Wright, John Ealing, Grace Vassello, Judith Eelloo, Alexander Lee
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引用次数: 0
WDR45 variants as a major cause for a clinically variable intellectual disability syndrome from early infancy in females. WDR45变体是导致女性从婴儿早期开始出现临床变异性智力残疾综合征的主要原因。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-28 DOI: 10.1136/jmg-2024-110068
Chihiro Abe-Hatano, Ken Inoue, Eri Takeshita, Yosuke Kawai, Katsushi Tokunaga, Yu-Ichi Goto

Pathogenic variants of WD repeat domain 45 (WDR45) cause neurodegeneration with brain iron accumulation 5 (NBIA5), which is characterised by progressive neurological regression and brain iron accumulation in adulthood. Early diagnosis of NBIA5 patients is difficult because they often show only a non-specific developmental delay in childhood, but it is essential for lifelong medical management. We investigated 32 females with developmental delays for coding variants of WDR45 using Sanger sequencing. Whole-genome sequencing (WGS) and X chromosome inactivation (XCI) analysis were also performed. We identified two disease-causing variants, one of which was a novel stop-loss variant, c.1051delG p.(Val351CysfsTer60), in a female with severe developmental delay from early infancy with epileptic spasms. The XCI analysis (which we originally developed) suggested a random pattern in white blood cells. WGS did not reveal any other pathogenic variants, including those in two iron transporter genes. Together with our previous findings in the WGS study, WDR45 variants accounted for 12% (6/51) of the females with developmental delay, suggesting that WDR45 is a major gene in females with developmental delay. Pathogenic variants of WDR45 result in various phenotypes that do not necessarily correlate with variant types or XCI skewing patterns.

WD重复结构域45(WDR45)的致病变体会导致脑铁积聚性神经变性5(NBIA5),其特征是成年后神经系统进行性退化和脑铁积聚。早期诊断 NBIA5 患者非常困难,因为他们在童年时期往往只表现出非特异性的发育迟缓,但这对终生医疗管理至关重要。我们利用桑格测序法对 32 名发育迟缓的女性进行了调查,以寻找 WDR45 的编码变异。同时还进行了全基因组测序(WGS)和X染色体失活(XCI)分析。我们发现了两个致病变体,其中一个是新的止损变体,c.1051delG p.(Val351CysfsTer60), 患有严重发育迟缓并伴有癫痫性痉挛的女性。XCI 分析(我们最初开发的)显示白细胞中存在随机模式。WGS 没有发现任何其他致病变体,包括两个铁转运体基因中的变体。结合我们之前在 WGS 研究中的发现,WDR45 变体占女性发育迟缓患者的 12%(6/51),这表明 WDR45 是女性发育迟缓患者的主要基因。WDR45的致病变异会导致各种表型,而这些表型并不一定与变异类型或XCI倾斜模式相关。
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引用次数: 0
Cardiac rhabdomyoma: a rare feature of Birt-Hogg-Dubé syndrome. 心脏横纹肌瘤:Birt-Hogg-Dubé 综合征的罕见特征。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-26 DOI: 10.1136/jmg-2024-110349
Florence Petit, Louise Devisme, Dimitri Tchernitchko, Olivia Domanski, Cecilia Gonzalez-Corcia, Lidwine Wemeau-Stervinou, Sophie Lejeune

Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal disorder, primarily characterised in adults by cutaneous features, pulmonary cysts that predispose to spontaneous pneumothorax and renal tumours. The syndrome is caused by pathogenic variants in the FLCN tumour suppressor gene, which plays a role in the mammalian target of rapamycin (mTOR) signalling pathway. We present the case of a newborn infant diagnosed with BHDS, who died of sudden cardiac death due to complications from cardiac rhabdomyoma. This is only the second reported case of such an association. Both cases were initially misdiagnosed with tuberous sclerosis complex, highlighting the diagnostic challenges. We discuss this differential diagnosis and suggest that cardiac rhabdomyomas, although rare, may be associated with BHDS and potentially life threatening. Therefore, we recommend cardiac screening in newborns at risk.

伯特-霍格-杜贝综合征(Birt-Hogg-Dubé Syndrome,BHDS)是一种罕见的常染色体疾病,成人患者主要表现为皮肤特征、易引发自发性气胸的肺囊肿和肾肿瘤。该综合征是由 FLCN 肿瘤抑制基因的致病变异引起的,该基因在哺乳动物雷帕霉素靶标(mTOR)信号通路中发挥作用。我们介绍了一例被诊断为 BHDS 的新生儿,他死于心脏横纹肌瘤并发症导致的心脏性猝死。这是仅有的第二例此类关联病例。两例病例最初都被误诊为结节性硬化综合征,这凸显了诊断上的挑战。我们对这一鉴别诊断进行了讨论,并提出心脏横纹肌瘤虽然罕见,但可能与 BHDS 相关,并可能威胁生命。因此,我们建议对有风险的新生儿进行心脏筛查。
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引用次数: 0
Accurate prenatal diagnosis of facioscapulohumeral muscular dystrophy 1 using nanopore sequencing. 利用纳米孔测序技术准确产前诊断面囊肱肌营养不良症1。
IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-26 DOI: 10.1136/jmg-2023-109832
Yanan Wang, Zhenhua Zhao, Fei Meng, Xiangdong Kong

Background: Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant muscular disorder mainly caused by the contraction and hypomethylation of the D4Z4 repeat array in chromosome 4q35. Prenatal diagnosis of FSHD1 is challenging due to the highly repetitive and long genomic structure. In this study, a pregnant woman diagnosed with FSHD1 using optical genome mapping sought assistance for a healthy offspring.

Methods: At the 17th week of gestation, she underwent amniocentesis, and genomic DNA (gDNA) was extracted from amniocytes. Whole-genome sequencing of the gDNA was performed using the nanopore MinION platform.

Results: Despite a sequencing depth of only 7.3×, bioinformatic analyses revealed that the fetus inherited four D4Z4 repeat units with the permissive 4qA from the mother and the eight D4Z4 repeat units with the non-permissive 4qB from the father. To validate the results, SNP-based linkage analyses were conducted with gDNA from the proband, the proband's father and proband's amniocytes. Results indicated that the fetus inherited the maternal pathogenic haplotype based on 144 informative SNPs. Linkage analysis was consistent with the nanopore sequencing.

Conclusion: Nanopore sequencing proves to be an accurate and direct method for genetic testing of monogenic diseases at the single-nucleotide level. This study represents the first application of nanopore sequencing in the prenatal diagnosis of FSHD1, providing a significant advantage for patients with de novo mutations.

背景:面岬肱肌营养不良症 1(FSHD1)是一种常染色体显性遗传的肌肉疾病,主要由染色体 4q35 上的 D4Z4 重复序列收缩和低甲基化引起。由于基因组结构高度重复且较长,FSHD1的产前诊断具有挑战性。在本研究中,一位孕妇通过光学基因组图谱诊断出患有 FSHD1,并希望获得健康的后代:在妊娠第 17 周时,她接受了羊膜穿刺术,并从羊膜细胞中提取了基因组 DNA(gDNA)。利用纳米孔 MinION 平台对 gDNA 进行了全基因组测序:结果:尽管测序深度仅为 7.3 倍,但生物信息学分析表明,胎儿从母亲那里遗传了 4 个 D4Z4 重复单位,其中 4qA 为允许遗传,而从父亲那里遗传了 8 个 D4Z4 重复单位,其中 4qB 为非允许遗传。为了验证这一结果,研究人员对来自疑似胎儿、疑似胎儿父亲和疑似胎儿羊膜细胞的 gDNA 进行了基于 SNP 的关联分析。结果表明,基于 144 个信息 SNP,胎儿遗传了母体的致病单倍型。关联分析与纳米孔测序结果一致:结论:纳米孔测序被证明是在单核苷酸水平上对单基因遗传病进行基因检测的一种准确而直接的方法。这项研究是纳米孔测序技术在 FSHD1 产前诊断中的首次应用,为新发基因突变患者提供了显著优势。
{"title":"Accurate prenatal diagnosis of facioscapulohumeral muscular dystrophy 1 using nanopore sequencing.","authors":"Yanan Wang, Zhenhua Zhao, Fei Meng, Xiangdong Kong","doi":"10.1136/jmg-2023-109832","DOIUrl":"https://doi.org/10.1136/jmg-2023-109832","url":null,"abstract":"<p><strong>Background: </strong>Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant muscular disorder mainly caused by the contraction and hypomethylation of the D4Z4 repeat array in chromosome 4q35. Prenatal diagnosis of FSHD1 is challenging due to the highly repetitive and long genomic structure. In this study, a pregnant woman diagnosed with FSHD1 using optical genome mapping sought assistance for a healthy offspring.</p><p><strong>Methods: </strong>At the 17th week of gestation, she underwent amniocentesis, and genomic DNA (gDNA) was extracted from amniocytes. Whole-genome sequencing of the gDNA was performed using the nanopore MinION platform.</p><p><strong>Results: </strong>Despite a sequencing depth of only 7.3×, bioinformatic analyses revealed that the fetus inherited four D4Z4 repeat units with the permissive 4qA from the mother and the eight D4Z4 repeat units with the non-permissive 4qB from the father. To validate the results, SNP-based linkage analyses were conducted with gDNA from the proband, the proband's father and proband's amniocytes. Results indicated that the fetus inherited the maternal pathogenic haplotype based on 144 informative SNPs. Linkage analysis was consistent with the nanopore sequencing.</p><p><strong>Conclusion: </strong>Nanopore sequencing proves to be an accurate and direct method for genetic testing of monogenic diseases at the single-nucleotide level. This study represents the first application of nanopore sequencing in the prenatal diagnosis of FSHD1, providing a significant advantage for patients with de novo mutations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502131","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
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
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。
{"title":"A novel pathogenic germline chromosome 3 inversion in von Hippel-Lindau disease.","authors":"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","doi":"10.1136/jmg-2024-110202","DOIUrl":"10.1136/jmg-2024-110202","url":null,"abstract":"<p><p>von Hippel-Lindau (VHL) is an autosomal-dominant hereditary tumour susceptibility disease associated with pathogenic germline variants in the <i>VHL</i> 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 <i>VHL</i> 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 <i>VHL</i> gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348350","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
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
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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Journal of Medical Genetics
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