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Clinical approach for managing patients with unexpected CDH1 mutations: A case report. 管理意外 CDH1 基因突变患者的临床方法:病例报告
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2496
Yago Garitaonaindia, Miriam Méndez, Fátima Valentín, Lourdes Gutiérrez, Alberto Herreros de Tejada, Antonio Sánchez Ruiz, Mariano Provencio, Atocha Romero

Background: Hereditary diffuse gastric cancer (HDGC) (OMIM# 137215) is an autosomal dominant cancer syndrome associated with CDH1 (OMIM# 192090) mutations. Prophylactic total gastrectomy (PTG) is the most recommended preventive treatment when a pathogenic mutation is found. However, the increasing use of genetic testing has led to the identification of incidental CDH1 mutations in individuals without a family history of gastric cancer. It remains unclear whether these patients should undergo prophylactic total gastrectomy.

Methods: Germline DNA, obtained from peripheral blood, was analysed by NGS.

Results: A 47-year-old woman was diagnosed with high-grade serous ovarian carcinoma, FIGO stage IIIC, with a Homologous Recombination Deficiency (HRD) GIS status of 78 (positive, cut-off: 43). She received chemotherapy and niraparib treatment. A multigene panel test revealed no pathogenic mutations in BRCA1 (OMIM# 113705)/BRCA2 (OMIM# 600185) genes, but a de novo deletion of exon 16 in CDH1 was found incidentally. She had no previous family history of gastric or breast cancer. The patient was enrolled in a surveillance program involving periodic endoscopy and was diagnosed with diffuse gastric cancer through biopsies of a pale area in the antrum after 1 year of close endoscopic follow-up.

Conclusion: This case presents supportive evidence for the pathogenic classification of the loss of the last exon of CDH1.

背景:遗传性弥漫性胃癌(HDGC)(OMIM# 137215)是一种常染色体显性癌症综合征,与 CDH1(OMIM# 192090)突变有关。当发现致病基因突变时,预防性全胃切除术(PTG)是最推荐的预防性治疗方法。然而,随着基因检测应用的不断增加,在无胃癌家族史的患者中偶然发现了 CDH1 基因突变。这些患者是否应该接受预防性全胃切除术,目前仍不清楚:从外周血中获得的种系 DNA 通过 NGS 进行分析:一名 47 岁女性被诊断为高级别浆液性卵巢癌,FIGO IIIC 期,同源重组缺陷(HRD)GIS 状态为 78(阳性,临界值:43)。她接受了化疗和尼拉帕利治疗。多基因面板检测显示,BRCA1(OMIM# 113705)/BRCA2(OMIM# 600185)基因没有致病突变,但偶然发现CDH1第16外显子有新缺失。她以前没有胃癌或乳腺癌家族史。患者参加了一项定期内镜检查的监测计划,经过一年的密切内镜随访,通过对胃窦苍白区域的活检确诊为弥漫性胃癌:本病例为 CDH1 最后一个外显子缺失的致病分类提供了支持性证据。
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引用次数: 0
Synonymous variant at the terminal nucleotide in exon 3 of F7 causes abnormal splicing: A case report. F7 第 3 外显子末端核苷酸的同义变异导致剪接异常:病例报告
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2492
Liya Wang, Wenshan Zeng, Yeqing Qian, Yixi Sun, Min Chen, Bei Liu, Junjie Hu, Ping Yu, Minyue Dong

Background: Synonymous variants are non-pathogenic due to non-substitution of amino acids. However, synonymous exonic terminal nucleotide substitutions may affect splicing. Splicing variants are easily analyzed at RNA level for genes expressed in blood cells. Minigene analysis provides another method for splicing variant analysis of genes that are poorly or not expressed in peripheral blood.

Methods: Whole exome sequencing was performed to screen for potential pathogenic mutations in the proband, which were validated within the family by Sanger sequencing. The pathogenicity of the synonymous mutation was analyzed using the minigene technology.

Results: The proband harbored the compound heterogeneous variants c. [291G >A; 572-50C >T] and c.681 + 1G >T in F7, of which the synonymous variant c.291G >A was located at the terminal position of exon 3. Minigene analysis revealed exon3 skipping due to this mutation, which may have subsequently affected protein sequence, structure, and function.

Conclusion: Our finding confirmed the pathogenicity of c.291G >A, thus extending the pathogenic mutation spectrum of F7, and providing insights for effective reproductive counseling.

背景:同义变异由于不替换氨基酸而不致病。然而,同义外显子末端核苷酸替换可能会影响剪接。对于在血细胞中表达的基因,剪接变异很容易在 RNA 水平上进行分析。微型基因分析为剪接变异分析提供了另一种方法,可用于分析外周血中表达较少或不表达的基因:方法:进行了全外显子组测序,以筛查潜在的致病基因突变,并通过桑格测序在家族内部进行了验证。利用微型基因技术分析了同义突变的致病性:结果:该患者在 F7 中携带有 c. [291G >A; 572-50C >T] 和 c.681 + 1G >T 的复合异质性变异,其中同义变异 c.291G >A 位于第 3 号外显子的末端位置。迷你基因分析表明,该突变导致了第3外显子的缺失,随后可能会影响蛋白质的序列、结构和功能:我们的发现证实了 c.291G >A 的致病性,从而扩展了 F7 的致病突变谱,并为有效的生殖咨询提供了启示。
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引用次数: 0
Clinical and genetic variability among Bulgarian patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay. 保加利亚常染色体隐性遗传性痉挛性共济失调(Charlevoix-Saguenay)患者的临床和遗传变异。
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2483
Teodora Chamova, Neviana Ivanova, Sylvia Cherninkova, Maya Koleva, Dora Zlatareva, Veneta Bojinova, Kalina Mihova, Martin Georgiev, Dilyan Ferdinandov, Stoyan Bichev, Radka Kaneva, Vanio Mitev, Albena Jordanova, Ivailo Tournev

Background: Autosomal recessive spastic ataxia ofCharlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterizedby early-onset cerebellar ataxia, peripheral sensorimotor neuropathy, and lowerlimb spasticity. We present clinical andgenetic data of the first Bulgarian patients diagnosed with ARSACS by wholeexome sequencing (WES).

Methods: Variant filtering was performed usinglocally established pipeline and the selected variants were analysed by Sangersequencing. All patients underwent clinical examination and testingincluding the standard rating scales for spastic paraplegia and ataxia.

Results: Five different SACS gene variants, three of which novel, have been identified inpatients from three different ethnic groups. In addition to the classicalclinical triad, brain MRI revealed cerebellar atrophy, linear pontineT2-hypointensities, and hyperintense rim lateral tothalamus combined with retinal nerve fiber layer thickening on opticcoherence tomography (OCT).

Conclusion: We expand the mutation, geographic, and phenotypic spectrum of ARSACS, adding Bulgaria to the world map of the disease, and drawing attention to the fact that it is still misdiagnosed. We demonstrated that brain MRI and OCT are necessary clinical tests for ARSACS diagnosis, even if one of the cardinal clinical features is lacking.

背景:常染色体隐性遗传性痉挛性共济失调(ARSACS)是一种罕见的神经退行性疾病,以早发性小脑共济失调、外周感觉运动神经病变和下肢痉挛为特征。我们介绍了首例通过全外显子组测序(WES)确诊的保加利亚 ARSACS 患者的临床和遗传学数据:方法:使用本地建立的流水线进行变异筛选,并通过桑格测序对筛选出的变异进行分析。所有患者均接受了临床检查和测试,包括痉挛性截瘫和共济失调的标准评分量表:结果:在来自三个不同种族的患者中发现了五种不同的 SACS 基因变异,其中三种是新型变异。除了经典的临床三联征外,脑部核磁共振成像(MRI)显示小脑萎缩、线性桥脑T2-高密度、眼球外侧高密度边缘,视网膜相干断层扫描(OCT)显示视网膜神经纤维层增厚:我们扩展了 ARSACS 的突变、地理和表型谱,为该病的世界地图增添了保加利亚的色彩,并提请人们注意该病仍被误诊的事实。我们证明,即使缺乏主要临床特征之一,脑部核磁共振成像和 OCT 也是诊断 ARSACS 的必要临床检查。
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引用次数: 0
A novel variant c.902C>A (p. A301D) in KCNQ4 associated with non-syndromic deafness 2A in a Chinese family. 一个中国家庭中与非综合征性耳聋 2A 相关的 KCNQ4 新变异 c.902C>A (p. A301D)。
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2446
Lingyan Ren, Jiangfen Wu, Ying Kuang, Kun Chen, Minmin Jiang, Zhaozhen Zhuo, Zuwei Cao, Shengwen Huang

Background: Deafness autosomal dominant 2A (DFNA2A) is related to non-syndromic genetic hearing impairment. The KCNQ4 (Potassium Voltage-Gated Channel Subfamily Q Member 4) can lead to DFNA2A. In this study, we report a case of autosomal dominant non-syndromic hearing loss with six family members as caused by a novel variant in the KCNQ4 gene.

Methods: The whole-exome sequencing (WES) and pure tone audiometry were performed on the proband of the family. Sanger sequencing was conducted on family members to determine if the novel variant in the KCNQ4 gene was present. Evolutionary conservation analysis and computational tertiary structure protein prediction of the wild-type KCNQ4 protein and its variant were then performed. In addition, voltage-gated channel activity of the wild-type KCNQ4 protein and its variant were tested using whole-cell patch clamp.

Results: It was observed that the proband had inherited autosomal dominant, non-syndromic sensorineural hearing loss as a trait. A novel co-segregating heterozygous missense variant (c.902C>A, p.Ala301Asp) of the KCNQ4 gene was identified in the proband and other five affected family members. This variant was predicted to cause an alanine-to-aspartic acid substitution at position 301 in the KCNQ4 protein. The alanine at position 301 is well conserved across different species. Whole-cell patch clamp showed that there was a significant difference between the WT protein currents and the mutant protein currents in the voltage-gated channel activity.

Conclusion: In the present study, performing WES in conjunction with Sanger sequencing enhanced the detection of a novel, potentially causative variant (c301 A>G; p.Ala301Asp) in exon 6 of the KCNQ4 gene. Therefore, our findings contributed to the mutation spectrum of the KCNQ4 gene and may be useful in the diagnosis and gene therapy of deafness autosomal dominant 2A.

背景:常染色体显性遗传性耳聋 2A(DFNA2A)与非综合征遗传性听力障碍有关。KCNQ4(钾电压门控通道 Q 亚家族成员 4)可导致 DFNA2A。在本研究中,我们报告了一例由 KCNQ4 基因的新型变异引起的常染色体显性遗传性听力损失病例,该病例有 6 名家族成员:方法:我们对该家族中的原发性患者进行了全基因组测序(WES)和纯音测听。对家族成员进行了 Sanger 测序,以确定是否存在 KCNQ4 基因的新型变异。然后对野生型 KCNQ4 蛋白及其变异体进行了进化保护分析和计算三级结构蛋白预测。此外,还使用全细胞膜片钳测试了野生型 KCNQ4 蛋白及其变体的电压门控通道活性:结果:研究发现,该患者为常染色体显性遗传的非综合征感音神经性听力损失。在该患者及其他五名受影响的家庭成员中,发现了 KCNQ4 基因的一个新的共分离杂合错义变体(c.902C>A, p.Ala301Asp)。据预测,该变异会导致 KCNQ4 蛋白中第 301 位的丙氨酸变成天冬氨酸。位于 301 位的丙氨酸在不同物种中具有良好的保守性。全细胞膜片钳显示,WT 蛋白电流与突变体蛋白电流的电压门控通道活性存在显著差异:在本研究中,在进行 WES 测序的同时进行 Sanger 测序,有助于在 KCNQ4 基因第 6 外显子中发现一个新的、潜在的致病变异(c301 A>G; p.Ala301Asp)。因此,我们的研究结果丰富了 KCNQ4 基因的突变谱,可能有助于常染色体显性 2A 耳聋的诊断和基因治疗。
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引用次数: 0
Prenatal diagnosis and genetic study of 22q11.2 microduplication in Chinese fetuses: A series of 31 cases and literature review. 中国胎儿 22q11.2 微重复的产前诊断和遗传学研究:31例系列病例及文献综述。
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2498
Xiali Jiang, Bin Liang, Shuqiong He, Xiaoqing Wu, Wantong Zhao, Huili Xue, Yan Wang, Na Lin, Hailong Huang, Liangpu Xu

Background: Patients with 22q11.2 microduplication syndrome exhibit a high degree of phenotypic heterogeneity and incomplete penetrance, making prenatal diagnosis challenging due to phenotypic variability. This report aims to raise awareness among prenatal diagnostic practitioners regarding the variant's complexity, providing a basis for prenatal genetic counseling.

Methods: Family and clinical data of 31 fetuses with 22q11.2 microduplications confirmed by chromosomal microarray between June 2017 and June 2023 were considered.

Results: Primary prenatal ultrasound features of affected fetuses include variable cardiac and cardiovascular anomalies, increased nuchal translucency (≥3 mm), renal abnormalities, and polyhydramnios. More than half of fetuses considered showed no intrauterine manifestations; therefore, prenatal diagnostic indicators were primarily advanced maternal age or high-risk Down syndrome screening. Most fetuses had microduplications in proximal or central 22q11.2 regions, with only three cases with distal microduplications. Among parents of fetuses considered, 87% (27/31) continued the pregnancy. During follow-up, 19 cases remained clinically asymptomatic.

Conclusion: Nonspecific 22q11.2 microduplication features in fetuses and its mild postnatal disease presentation highlight the need to cautiously approach prenatal diagnosis and pregnancy decision-making. Increased clinical efforts should be made regarding providing parents with specialized genetic counseling, long-term follow-up, and fetal risk information.

背景:22q11.2微重复综合征患者表现出高度的表型异质性和不完全渗透性,由于表型变异,产前诊断具有挑战性。本报告旨在提高产前诊断从业人员对该变异复杂性的认识,为产前遗传咨询提供依据:方法:考虑了2017年6月至2023年6月期间31例经染色体芯片确认的22q11.2微重复胎儿的家族和临床数据:受影响胎儿的主要产前超声特征包括不同的心脏和心血管异常、颈项透明带增加(≥3 mm)、肾脏异常和多羊水。超过一半的胎儿没有宫内表现,因此产前诊断指标主要是高龄产妇或高风险唐氏综合征筛查。大多数胎儿的微重复位于 22q11.2 近端或中心区域,只有 3 例胎儿的微重复位于远端。在考虑的胎儿父母中,87%(27/31)继续妊娠。在随访过程中,19 例仍无临床症状:结论:胎儿的非特异性 22q11.2 微重复特征及其轻微的产后疾病表现突显了谨慎对待产前诊断和妊娠决策的必要性。临床上应加强为父母提供专门的遗传咨询、长期随访和胎儿风险信息。
{"title":"Prenatal diagnosis and genetic study of 22q11.2 microduplication in Chinese fetuses: A series of 31 cases and literature review.","authors":"Xiali Jiang, Bin Liang, Shuqiong He, Xiaoqing Wu, Wantong Zhao, Huili Xue, Yan Wang, Na Lin, Hailong Huang, Liangpu Xu","doi":"10.1002/mgg3.2498","DOIUrl":"10.1002/mgg3.2498","url":null,"abstract":"<p><strong>Background: </strong>Patients with 22q11.2 microduplication syndrome exhibit a high degree of phenotypic heterogeneity and incomplete penetrance, making prenatal diagnosis challenging due to phenotypic variability. This report aims to raise awareness among prenatal diagnostic practitioners regarding the variant's complexity, providing a basis for prenatal genetic counseling.</p><p><strong>Methods: </strong>Family and clinical data of 31 fetuses with 22q11.2 microduplications confirmed by chromosomal microarray between June 2017 and June 2023 were considered.</p><p><strong>Results: </strong>Primary prenatal ultrasound features of affected fetuses include variable cardiac and cardiovascular anomalies, increased nuchal translucency (≥3 mm), renal abnormalities, and polyhydramnios. More than half of fetuses considered showed no intrauterine manifestations; therefore, prenatal diagnostic indicators were primarily advanced maternal age or high-risk Down syndrome screening. Most fetuses had microduplications in proximal or central 22q11.2 regions, with only three cases with distal microduplications. Among parents of fetuses considered, 87% (27/31) continued the pregnancy. During follow-up, 19 cases remained clinically asymptomatic.</p><p><strong>Conclusion: </strong>Nonspecific 22q11.2 microduplication features in fetuses and its mild postnatal disease presentation highlight the need to cautiously approach prenatal diagnosis and pregnancy decision-making. Increased clinical efforts should be made regarding providing parents with specialized genetic counseling, long-term follow-up, and fetal risk information.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 7","pages":"e2498"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Multisystem disorder associated with a pathogenic variant in CLCN7 in the absence of osteopetrosis. 与 CLCN7 的一个致病变体有关的多系统疾病,但没有骨化症。
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2494
Chung-Lin Lee, Yeun-Wen Chang, Hsiang-Yu Lin, Hung-Chang Lee, Ting-Chi Yeh, Li-Ching Fang, Ni-Chung Lee, Jeng-Daw Tsai, Shuan-Pei Lin

Background: We clinically and genetically evaluated a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. Whole-exome sequencing revealed a de novo gain-of-function variant, p.Tyr715Cys, in the C-terminal domain of ClC-7 encoded by CLCN7.

Methods: Nicoli et al. (2019) assessed the functional impact of p.Tyr715Cys by heterologous expression in Xenopus oocytes and evaluating resulting currents.

Results: The variant led to increased outward currents, indicating it underlies the patient's phenotype of lysosomal hyperacidity, storage defects and vacuolization. This demonstrates the crucial physiological role of ClC-7 antiporter activity in maintaining appropriate lysosomal pH.

Conclusion: Elucidating mechanisms by which CLCN7 variants lead to lysosomal dysfunction will advance understanding of genotype-phenotype correlations. Identifying modifier genes and compensatory pathways may reveal therapeutic targets. Ongoing functional characterization of variants along with longitudinal clinical evaluations will continue advancing knowledge of ClC-7's critical roles and disease mechanisms resulting from its dysfunction. Expanded cohort studies are warranted to delineate the full spectrum of associated phenotypes.

背景:我们对一名患有发育迟缓、器官肥大、低丙种球蛋白血症和色素沉着的台湾男孩进行了临床和遗传学评估。全外显子组测序发现,CLCN7编码的ClC-7的C-末端结构域存在一个新功能增益变异p.Tyr715Cys:Nicoli等人(2019)通过在爪蟾卵母细胞中异源表达p.Tyr715Cys并评估所产生的电流,评估了其功能影响:结果:该变异导致外向电流增加,表明它是患者溶酶体酸度过高、储存缺陷和空泡化表型的基础。这证明了 ClC-7 反转运体活性在维持溶酶体适当 pH 值方面的关键生理作用:结论:阐明CLCN7变体导致溶酶体功能障碍的机制将促进对基因型与表型相关性的理解。确定修饰基因和代偿途径可能会揭示治疗目标。对变异体的持续功能表征以及纵向临床评估将继续增进人们对 ClC-7 关键作用及其功能障碍导致的疾病机制的了解。有必要扩大队列研究范围,以确定相关表型的全部范围。
{"title":"Multisystem disorder associated with a pathogenic variant in CLCN7 in the absence of osteopetrosis.","authors":"Chung-Lin Lee, Yeun-Wen Chang, Hsiang-Yu Lin, Hung-Chang Lee, Ting-Chi Yeh, Li-Ching Fang, Ni-Chung Lee, Jeng-Daw Tsai, Shuan-Pei Lin","doi":"10.1002/mgg3.2494","DOIUrl":"10.1002/mgg3.2494","url":null,"abstract":"<p><strong>Background: </strong>We clinically and genetically evaluated a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. Whole-exome sequencing revealed a de novo gain-of-function variant, p.Tyr715Cys, in the C-terminal domain of ClC-7 encoded by CLCN7.</p><p><strong>Methods: </strong>Nicoli et al. (2019) assessed the functional impact of p.Tyr715Cys by heterologous expression in Xenopus oocytes and evaluating resulting currents.</p><p><strong>Results: </strong>The variant led to increased outward currents, indicating it underlies the patient's phenotype of lysosomal hyperacidity, storage defects and vacuolization. This demonstrates the crucial physiological role of ClC-7 antiporter activity in maintaining appropriate lysosomal pH.</p><p><strong>Conclusion: </strong>Elucidating mechanisms by which CLCN7 variants lead to lysosomal dysfunction will advance understanding of genotype-phenotype correlations. Identifying modifier genes and compensatory pathways may reveal therapeutic targets. Ongoing functional characterization of variants along with longitudinal clinical evaluations will continue advancing knowledge of ClC-7's critical roles and disease mechanisms resulting from its dysfunction. Expanded cohort studies are warranted to delineate the full spectrum of associated phenotypes.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 7","pages":"e2494"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11273547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Glucose-6-phosphate dehydrogenase deficiency as a cause for nonimmune hydrops fetalis and severe fetal anemia: A systematic review. 葡萄糖-6-磷酸脱氢酶缺乏症是导致非免疫性胎儿水肿和严重胎儿贫血的原因之一:系统综述。
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2491
Neel S Iyer, Matthew H Mossayebi, Tracy J Gao, Lylach Haizler-Cohen, Daniele Di Mascio, Rodney A McLaren, Huda B Al-Kouatly

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disorder that predisposes individuals to hemolysis due to an inborn error of metabolism. We performed a systematic literature review to evaluate G6PD deficiency as a possible etiology of nonimmune hydrops fetalis (NIHF) and severe fetal anemia.

Methods: PubMed, OVID Medline, Scopus, and clinicaltrials.gov were queried from inception until 31 April 2023 for all published cases of NIHF and severe fetal anemia caused by G6PD deficiency. Keywords included "fetal edema," "hydrops fetalis," "glucose 6 phosphate dehydrogenase deficiency," and "fetal anemia." Cases with workup presuming G6PD deficiency as an etiology for NIHF and severe fetal anemia were included. PRISMA guidelines were followed.

Results: Five cases of G6PD-related NIHF and one case of severe fetal anemia were identified. Four fetuses (4/6, 66.7%) were male and two fetuses (2/6, 33.3%) were female. Mean gestational age at diagnosis of NIHF/anemia and delivery was 32.2 ± 4.9 and 35.7 ± 2.4 weeks, respectively. Four cases (66.7%) required a cordocentesis for fetal transfusion, and two cases (33.3%) received blood transfusions immediately following delivery. Among the four multigravida cases, two (50%) noted previous pregnancies complicated by neonatal anemia. When reported, the maternal cases included two G6PD deficiency carrier patients and two G6PD-deficient patients. Exposures to substances known to cause G6PD deficiency-related hemolysis occurred in 3/6 (50%) cases.

Conclusion: Six cases of NIHF/severe fetal anemia were associated with G6PD deficiency. While G6PD deficiency is an X-linked recessive condition, female fetuses can be affected. Fetal G6PD deficiency testing can be considered if parental history indicates, particularly if the standard workup for NIHF is negative.

背景:葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症是一种 X 连锁隐性遗传疾病,由于先天性代谢错误,患者容易发生溶血。我们进行了一项系统性文献综述,以评估 G6PD 缺乏症作为非免疫性胎儿水肿(NIHF)和严重胎儿贫血的可能病因:方法:查询了 PubMed、OVID Medline、Scopus 和 clinicaltrials.gov,以了解从开始到 2023 年 4 月 31 日所有已发表的由 G6PD 缺乏引起的非免疫性胎儿水肿和严重胎儿贫血病例。关键词包括 "胎儿水肿"、"胎儿水肿"、"葡萄糖-6 磷酸脱氢酶缺乏 "和 "胎儿贫血"。纳入的病例均推测 G6PD 缺乏是 NIHF 和严重胎儿贫血的病因。结果结果:共发现 5 例 G6PD 相关 NIHF 和 1 例严重胎儿贫血。四个胎儿(4/6,66.7%)为男性,两个胎儿(2/6,33.3%)为女性。确诊NIHF/贫血和分娩时的平均孕周分别为(32.2 ± 4.9)周和(35.7 ± 2.4)周。四名产妇(66.7%)需要进行脐带穿刺为胎儿输血,两名产妇(33.3%)在分娩后立即接受了输血。在 4 例多胎妊娠中,有 2 例(50%)曾在怀孕时并发新生儿贫血。在报告的产妇病例中,包括两名 G6PD 缺乏症携带者和两名 G6PD 缺乏症患者。3/6(50%)的病例接触了已知会导致 G6PD 缺乏症相关溶血的物质:结论:6 例 NIHF/重度胎儿贫血与 G6PD 缺乏有关。虽然 G6PD 缺乏症是一种 X 连锁隐性遗传病,但女性胎儿也可能受到影响。如果父母病史提示,尤其是在 NIHF 的标准检查结果为阴性时,可考虑进行胎儿 G6PD 缺乏症检测。
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引用次数: 0
Targeted next-generation sequencing reveals the genetic mechanism of Chinese Marfan syndrome cohort with ocular manifestation. 靶向新一代测序揭示中国马凡氏综合征队列眼部表现的遗传机制。
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2482
Dongming Han, Ziwei Wang, Xuan Chen, Zijia Liu, Zhengtao Yang, Yixi Chen, Peiyi Tian, Jiankang Li, ZhuoShi Wang

Background: Marfan syndrome (MFS) is a hereditary connective tissue disorder involving multiple systems, including ophthalmologic abnormalities. Most cases are due to heterozygous mutations in the fibrillin-1 gene (FBN1). Other associated genes include LTBP2, MYH11, MYLK, and SLC2A10. There is significant clinical overlap between MFS and other Marfan-like disorders.

Purpose: To expand the mutation spectrum of FBN1 gene and validate the pathogenicity of Marfan-related genes in patients with MFS and ocular manifestations.

Methods: We recruited 318 participants (195 cases, 123 controls), including 59 sporadic cases and 88 families. All patients had comprehensive ophthalmic examinations showing ocular features of MFS and met Ghent criteria. Additionally, 754 cases with other eye diseases were recruited. Panel-based next-generation sequencing (NGS) screened mutations in 792 genes related to inherited eye diseases.

Results: We detected 181 mutations with an 84.7% detection rate in sporadic cases and 87.5% in familial cases. The overall detection rate was 86.4%, with FBN1 accounting for 74.8%. In cases without FBN1 mutations, 23 mutations from seven Marfan-related genes were identified, including four pathogenic or likely pathogenic mutations in LTBP2. The 181 mutations included 165 missenses, 10 splicings, three frameshifts, and three nonsenses. FBN1 accounted for 53.0% of mutations. The most prevalent pathogenic mutation was FBN1 c.4096G>A. Additionally, 94 novel mutations were detected, with 13 de novo mutations in 14 families.

Conclusion: We expanded the mutation spectrum of the FBN1 gene and provided evidence for the pathogenicity of other Marfan-related genes. Variants in LTBP2 may contribute to the ocular manifestations in MFS, underscoring its role in phenotypic diversity.

背景:马凡综合征(MFS)是一种遗传性结缔组织疾病,涉及多个系统,包括眼科异常。大多数病例是由于纤连蛋白-1基因(FBN1)的杂合子突变所致。其他相关基因包括 LTBP2、MYH11、MYLK 和 SLC2A10。目的:扩大 FBN1 基因的突变谱,验证马凡氏相关基因在 MFS 和眼部表现患者中的致病性:我们招募了 318 名参与者(195 例病例,123 例对照),其中包括 59 例散发性病例和 88 个家族。所有患者均接受了全面的眼科检查,显示出 MFS 的眼部特征,并符合根特标准。此外,还招募了 754 例患有其他眼部疾病的病例。基于面板的新一代测序(NGS)筛查了与遗传性眼病相关的 792 个基因的突变:我们发现了 181 个基因突变,散发性病例的检出率为 84.7%,家族性病例的检出率为 87.5%。总检出率为 86.4%,其中 FBN1 占 74.8%。在没有FBN1突变的病例中,从7个马凡氏相关基因中发现了23个突变,包括LTBP2中的4个致病或可能致病的突变。这181个突变包括165个错义、10个剪接、3个框移和3个非错义。FBN1占突变的53.0%。最常见的致病突变是 FBN1 c.4096G>A。此外,还发现了94个新突变,其中14个家族中有13个新突变:结论:我们扩大了 FBN1 基因的突变谱,并为其他马凡氏相关基因的致病性提供了证据。LTBP2基因的变异可能导致了MFS的眼部表现,突出了其在表型多样性中的作用。
{"title":"Targeted next-generation sequencing reveals the genetic mechanism of Chinese Marfan syndrome cohort with ocular manifestation.","authors":"Dongming Han, Ziwei Wang, Xuan Chen, Zijia Liu, Zhengtao Yang, Yixi Chen, Peiyi Tian, Jiankang Li, ZhuoShi Wang","doi":"10.1002/mgg3.2482","DOIUrl":"10.1002/mgg3.2482","url":null,"abstract":"<p><strong>Background: </strong>Marfan syndrome (MFS) is a hereditary connective tissue disorder involving multiple systems, including ophthalmologic abnormalities. Most cases are due to heterozygous mutations in the fibrillin-1 gene (FBN1). Other associated genes include LTBP2, MYH11, MYLK, and SLC2A10. There is significant clinical overlap between MFS and other Marfan-like disorders.</p><p><strong>Purpose: </strong>To expand the mutation spectrum of FBN1 gene and validate the pathogenicity of Marfan-related genes in patients with MFS and ocular manifestations.</p><p><strong>Methods: </strong>We recruited 318 participants (195 cases, 123 controls), including 59 sporadic cases and 88 families. All patients had comprehensive ophthalmic examinations showing ocular features of MFS and met Ghent criteria. Additionally, 754 cases with other eye diseases were recruited. Panel-based next-generation sequencing (NGS) screened mutations in 792 genes related to inherited eye diseases.</p><p><strong>Results: </strong>We detected 181 mutations with an 84.7% detection rate in sporadic cases and 87.5% in familial cases. The overall detection rate was 86.4%, with FBN1 accounting for 74.8%. In cases without FBN1 mutations, 23 mutations from seven Marfan-related genes were identified, including four pathogenic or likely pathogenic mutations in LTBP2. The 181 mutations included 165 missenses, 10 splicings, three frameshifts, and three nonsenses. FBN1 accounted for 53.0% of mutations. The most prevalent pathogenic mutation was FBN1 c.4096G>A. Additionally, 94 novel mutations were detected, with 13 de novo mutations in 14 families.</p><p><strong>Conclusion: </strong>We expanded the mutation spectrum of the FBN1 gene and provided evidence for the pathogenicity of other Marfan-related genes. Variants in LTBP2 may contribute to the ocular manifestations in MFS, underscoring its role in phenotypic diversity.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 7","pages":"e2482"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
A novel variant in the FLCN gene in a Chinese family with Birt-Hogg-Dubé syndrome. 一个中国 Birt-Hogg-Dubé 综合征家族中的 FLCN 基因新变异。
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2488
He Miao, Yulin Zhou, Silun Ge, Yufeng Gu, Le Qu, Wenquan Zhou, Haowei He

Background: This study aimed to identify disease-causing variants within a Chinese family affected by Birt-Hogg-Dubé syndrome (BHDS), which arises from an autosomal dominant inheritance pattern attributed to variants in the folliculin (FLCN) gene, recognized as a tumor suppressor gene.

Methods: A Chinese proband diagnosed with BHDS due to renal tumors underwent next-generation sequencing (NGS), revealing a novel variant in the FLCN gene. Sanger sequencing was subsequently performed on blood samples obtained from family members to confirm the presence of this variant.

Results: A novel germline frameshift variant (NM_144997.5:c.977dup) was identified in five individuals among the screened family members, marking the first report of this variant. Additionally, a somatic frameshift variant (NM_144997.5:c.1252del) was detected in the renal tumors of the proband. No variant was detected in unaffected family members.

Conclusions: A novel heterozygous variant was identified in exon 9 of the FLCN gene, which broadens the spectrum of FLCN variants. We recommend that molecular analysis of the FLCN gene be performed in patients with suspected BHDS and their families.

研究背景BHDS是一种常染色体显性遗传模式,由被认为是肿瘤抑制基因的蓇葖果素(FLCN)基因变异引起:一名因肾脏肿瘤而被诊断为 BHDS 的中国原发性患者接受了新一代测序(NGS),发现了 FLCN 基因中的一个新型变异。随后对家庭成员的血液样本进行了桑格测序,以确认该变异的存在:结果:在筛查出的家庭成员中,有五名个体发现了一个新型生殖系框移变异体(NM_144997.5:c.977dup),这也是该变异体的首次报告。此外,还在该患者的肾脏肿瘤中检测到一个体细胞框架移位变体(NM_144997.5:c.1252del)。在未受影响的家庭成员中未发现变异:结论:在FLCN基因第9外显子中发现了一个新的杂合变异体,这扩大了FLCN变异体的范围。我们建议对疑似 BHDS 患者及其家属进行 FLCN 基因分子分析。
{"title":"A novel variant in the FLCN gene in a Chinese family with Birt-Hogg-Dubé syndrome.","authors":"He Miao, Yulin Zhou, Silun Ge, Yufeng Gu, Le Qu, Wenquan Zhou, Haowei He","doi":"10.1002/mgg3.2488","DOIUrl":"10.1002/mgg3.2488","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to identify disease-causing variants within a Chinese family affected by Birt-Hogg-Dubé syndrome (BHDS), which arises from an autosomal dominant inheritance pattern attributed to variants in the folliculin (FLCN) gene, recognized as a tumor suppressor gene.</p><p><strong>Methods: </strong>A Chinese proband diagnosed with BHDS due to renal tumors underwent next-generation sequencing (NGS), revealing a novel variant in the FLCN gene. Sanger sequencing was subsequently performed on blood samples obtained from family members to confirm the presence of this variant.</p><p><strong>Results: </strong>A novel germline frameshift variant (NM_144997.5:c.977dup) was identified in five individuals among the screened family members, marking the first report of this variant. Additionally, a somatic frameshift variant (NM_144997.5:c.1252del) was detected in the renal tumors of the proband. No variant was detected in unaffected family members.</p><p><strong>Conclusions: </strong>A novel heterozygous variant was identified in exon 9 of the FLCN gene, which broadens the spectrum of FLCN variants. We recommend that molecular analysis of the FLCN gene be performed in patients with suspected BHDS and their families.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 7","pages":"e2488"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11222970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
A compound heterozygote case of glutaric aciduria type II in a patient carrying a novel candidate variant in ETFDH gene: A case report and literature review on compound heterozygote cases. 一名携带 ETFDH 基因新型候选变体的戊二酸尿症 II 型复合杂合子病例:一份病例报告和有关复合杂合子病例的文献综述。
IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-07-01 DOI: 10.1002/mgg3.2489
Mohammad Reza Seyedtaghia, Reza Jafarzadeh-Esfehani, Seyedmojtaba Hosseini, Sepehr Kobravi, Mahdis Hakkaki, Yalda Nilipour

Background: Glutaric aciduria type II (GA2) is a rare genetic disorder inherited in an autosomal recessive manner. Double dosage mutations in GA2 corresponding genes, ETFDH, ETFA, and ETFB, lead to defects in the catabolism of fatty acids, and amino acids lead to broad-spectrum phenotypes, including muscle weakness, developmental delay, and seizures. product of these three genes have crucial role in transferring electrons to the electron transport chain (ETC), but are not directly involve in ETC complexes.

Methods: Here, by using exome sequencing, the cause of periodic cryptic gastrointestinal complications in a 19-year-old girl was resolved after years of diagnostic odyssey. Protein modeling for the novel variant served as another line of validation for it.

Results: Exome Sequencing (ES) identified two variants in ETFDH: ETFDH:c.926T>G and ETFDH:c.1141G>C. These variants are likely contributing to the crisis in this case. To the best of our knowledge at the time of writing this manuscript, variant ETFDH:c.926T>G is reported here for the first time. Clinical manifestations of the case and pathological analysis are in consistent with molecular findings. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant. ETFDH:c.926T>G is reported here for the first time in relation to the causation GA2.

Conclusion: Given the milder symptoms in this case, a review of GA2 cases caused by compound heterozygous mutations was conducted, highlighting the range of symptoms observed in these patients, from mild fatigue to more severe outcomes. The results underscore the importance of comprehensive genetic analysis in elucidating the spectrum of clinical presentations in GA2 and guiding personalized treatment strategies.

背景:戊二酸尿症 II 型(GA2)是一种罕见的常染色体隐性遗传疾病。GA2相应基因ETFDH、ETFA和ETFB的双剂量突变会导致脂肪酸和氨基酸的分解缺陷,从而导致包括肌无力、发育迟缓和癫痫在内的广泛表型。这三个基因的产物在向电子传递链(ETC)传递电子方面起着至关重要的作用,但并不直接参与 ETC 复合物。方法:在此,通过外显子组测序,经过多年的诊断探索,解决了一名 19 岁女孩周期性隐性胃肠道并发症的病因。对该新型变异体的蛋白质建模是对该变异体的另一种验证:外显子组测序(ES)发现了两个ETFDH变异:ETFDH:c.926T>G和ETFDH:c.1141G>C。这些变异很可能导致了本病例中的危机。据我们撰写本稿件时所知,变异ETFDH:c.926T>G是首次报道。该病例的临床表现和病理分析与分子研究结果一致。蛋白质模型为证明该新型变异体的致病性提供了另一个证据。本文首次报道了 ETFDH:c.926T>G 与 GA2 的致病关系:鉴于该病例的症状较轻,我们对由复合杂合子突变引起的 GA2 病例进行了回顾,强调了在这些患者中观察到的症状范围,从轻度疲劳到更严重的结果。研究结果强调了全面基因分析在阐明GA2临床表现范围和指导个性化治疗策略方面的重要性。
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引用次数: 0
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Molecular Genetics & Genomic Medicine
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