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RPL26 variants: A rare cause of Diamond-Blackfan anemia syndrome with multiple congenital anomalies at the forefront RPL26变体:菱形-黑方贫血综合征的罕见病因,多种先天性畸形并存。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-10 DOI: 10.1016/j.gim.2024.101266
Clémence Vanlerberghe , Frédéric Frénois , Thomas Smol , Anne-Sophie Jourdain , Fabienne Escande , Emilie Aït-Yahya , Abdulrahman A. Aldeeri , Timothy W. Yu , Valérie Cormier-Daire , Jamal Ghoumid , Maureen Jacob , Ruth Newbury-Ecob , Sylvie Manouvrier , Jessica Platon , Sebastian Sailer , Perrine Brunelle , Lydie Da Costa , Florence Petit

Purpose

Diamond-Blackfan anemia syndrome (DBS) is a rare congenital disorder originally characterized by bone marrow failure with or without various congenital anomalies. At least 24 genes are implicated, the vast majority encoding for ribosomal proteins. RPL26 (ribosomal protein L26) is an emerging candidate (DBA11, MIM#614900). We aim to further delineate this rare condition.

Methods

Patients carrying heterozygous RPL26 variants were recruited. In one of them, erythroid proliferation and differentiation from peripheral blood CD34+ cells were studied by flow cytometry, and RPL26 expression by quantitative reverse transcription polymerase chain reaction and immunoblotting.

Results

We report on 8 affected patients from 4 families. Detailed phenotyping reveals that RPL26 is mainly associated with multiple congenital anomalies (particularly radial ray anomalies), albeit with variable expression. Mandibulofacial dysostosis and neural tube defects are potential features in DBA11, expanding the growing list of DBS abnormalities. In 1 individual, we showed that RPL26 haploinsufficiency was responsible for subclinical impairment in erythroid proliferation and enucleation. The absence of hematological involvement in 4 adults from this series contributes to the mounting evidence that bone marrow failure is not universally central to all DBS genes.

Conclusion

We confirm RPL26 as a DBS gene and expand the phenotypic spectrum of the gene and the disease.
目的:钻石-布莱克范贫血综合征(DBS)是一种罕见的先天性疾病,最初以骨髓衰竭为特征,伴有或不伴有各种先天性异常。至少有 24 个基因与此病有关,其中绝大多数为核糖体蛋白编码。RPL26(核糖体蛋白 L26)是一个新出现的候选基因(DBA11,MIM#614900)。方法招募了携带杂合子 RPL26 变体的患者。其中一人的外周血 CD34+ 细胞的红细胞增殖和分化情况通过流式细胞术进行了研究,RPL26 的表达情况通过 qRT-PCR 和免疫印迹法进行了研究。详细的表型分析表明,RPL26 主要与多种先天性畸形(尤其是桡骨射线畸形)有关,但其表达可变。下颌骨面部发育不良和神经管缺陷是 DBA11 的潜在特征,从而扩大了 DBS 异常的范围。在一个个体中,我们发现 RPL26 单倍体缺失是导致红细胞增殖和去核的亚临床损害的原因。我们证实 RPL26 是一种 DBS 基因,并扩大了该基因和该疾病的表型范围。
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引用次数: 0
Functional characterization vs in silico prediction for TBX5 missense and splice variants in Holt-Oram syndrome 霍尔特-奥拉姆综合征中 TBX5 错义和剪接变体的功能表征与硅学预测。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-10 DOI: 10.1016/j.gim.2024.101267
Clémence Vanlerberghe , Anne Sophie Jourdain , Frédéric Frenois , Emilie Ait-Yahya , Mike Bamshad , Anne Dieux , William Dufour , Fiona Leduc , Sylvie Manouvrier-Hanu , Karynne Patterson , Jamal Ghoumid , Fabienne Escande , Thomas Smol , Perrine Brunelle , Florence Petit

Purpose

Predicting effects of genomic variants has become a real challenge in the diagnosis of rare human diseases. Holt-Oram syndrome is an autosomal condition characterized by the association of radial and heart defects, due to variants in TBX5. Most variants are predicted to be truncating and result in haploinsufficiency. The pathogenicity of missense or splice variants is harder to demonstrate.

Methods

Fourteen TBX5 variants of uncertain significance (5 missense, 9 splice) and 6 likely pathogenic missense variants were selected for functional testing, depending on the variant-type (immunolocalization, western blot, reporter assays, minigene splice assays, and reverse transcription-polymerase chain reaction). Results were compared with in silico predictions.

Results

Functional tests allowed to reclassify 9/14 variants of uncertain significance in TBX5 as likely pathogenic, confirming their role in Holt-Oram syndrome. We demonstrated loss of function (n = 8) or gain of function (n = 1) for 9 of the 11 missense variants, whereas no functional impact was shown for the 2 variants: p.(Gly195Ala) and p.(Ser261Cys), as suggested by contradictory predictions of in silico approaches. Of 9 splice variants predicted to affect splicing by SpliceAI, we observed partial or complete exon skipping (n = 6), intron retention (n = 2) or exon shortening (n = 1), inducing frame shifting with premature stop codons.

Conclusion

Bioinformatic and biological approaches are complementary, together with a good knowledge of clinical conditions, for accurate American College of Medical Genetics and Genomics classification in human rare diseases.
目的预测基因组变异的影响已成为人类罕见疾病诊断的真正挑战。霍尔特-奥拉姆综合征(Holt-Oram syndrome,HOS)是一种常染色体疾病,其特征是由于 TBX5 的变异而导致桡骨和心脏缺陷。大多数变异被预测为截断变异,并导致单倍体缺陷。方法根据变体类型(免疫定位、Western 印迹、报告基因检测、迷你基因剪接检测和 RT-PCR),选择了 14 个意义不确定的 TBX5 变异(VUS)(5 个错义变体、9 个剪接变体)和 6 个可能致病的错义变体进行功能检测。结果功能测试将 TBX5 中的 9/14 个 VUS 重新归类为可能致病的基因,证实了它们在 HOS 中的作用。我们证明了 11 个错义变异中 9 个的功能缺失(n=8)或功能增益(n=1),而 2 个变异:p.(Gly195Ala) 和 p.(Ser261Cys)则未显示出功能影响,这与硅学方法的预测相互矛盾。在 SpliceAI 预测会影响剪接的 9 个剪接变异中,我们观察到了部分或完全的外显子跳过(n=6)、内含子保留(n=2)或外显子缩短(n=1),诱发了过早终止密码子的框架转换。
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引用次数: 0
Advanced practice providers in the medical genetics workforce: A nationwide survey 医学遗传学工作者中的高级执业医师:全国调查。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-10 DOI: 10.1016/j.gim.2024.101254
Wesley G. Patterson , Stephanie J. Offord , Laura D. Buch , Gina M. Lewis , Ashley Andrews , Kaelyn B. Sparks , Jessica A. Cooley Coleman , Leta M. Tribble

Purpose

This study characterizes the current landscape of genetics advanced practice providers (APPs) in the United States.

Methods

A 35-question survey was emailed to the Genetics APP Listserv in the fall of 2023. Questions represented 5 domains: demographics, practice, onboarding, compensation, and perceptions.

Results

A total of 105 genetics APPs (93%) completed the survey. Genetics APPs evaluate various patient types and populations in multiple settings, working an average of 41.3 hours and seeing 15 patients weekly. Nearly all see new (96%) and follow-up (98%) patients and utilize telemedicine (93%). Half (51%) have only worked in the genetics specialty during their career. Overall, APPs are generally satisfied with their career as a genetics APP (98%) and work-life balance (86%), and most (86%) feel that they function at the top of their scope.

Conclusion

Study findings elucidate the current state of genetics APPs. Results define the characteristics and role of an APP in the genetics specialty and will guide employers and genetics organizations to utilize APPs at the top of their scope and recruit new APPs to this exciting field. A collaborative effort is needed to increase the overall genetics workforce, decrease patient wait times, and increase access to genetics care.
目的本研究描述了美国遗传学高级实践提供者(APP)的现状。方法2023 年秋季,通过电子邮件向遗传学 APP 列表服务器发送了 35 个问题的调查问卷。结果共有 105 名遗传学 APP(93%)完成了调查。遗传学 APP 在多种环境下评估各种类型的患者和人群,平均工作时间为 41.3 小时,每周接诊 15 名患者。几乎所有 APP 都会接诊新患者(96%)和复诊患者(98%),并使用远程医疗(93%)。半数(51%)在其职业生涯中只在遗传学专科工作过。总体而言,APPs 对其作为遗传学 APPs 的职业生涯(98%)和工作与生活的平衡(86%)普遍感到满意,大多数(86%)APPs 认为自己在其工作范围内发挥了最大作用。研究结果明确了遗传学专业 APP 的特点和作用,并将指导雇主和遗传学组织充分利用 APP,为这一令人兴奋的领域招募新的 APP。我们需要通力合作,以增加遗传学专业的整体人才队伍,缩短患者的等待时间,并增加遗传学医疗服务的可及性。
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引用次数: 0
Parents' experiences with sequencing of all known pediatric cancer predisposition genes in children with cancer 癌症患儿家长对所有已知儿科癌症易感基因进行测序的经验。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-05 DOI: 10.1016/j.gim.2024.101250
S.B.B. Bon , R.H.P. Wouters , J.J. Bakhuizen , M.M. van den Heuvel-Eibrink , H. Maurice-Stam , M.C.J. Jongmans , M.A. Grootenhuis

Purpose

Germline DNA sequencing is increasingly used within pediatric oncology, yet parental experiences remain underexplored.

Methods

Parents of children undergoing cancer predisposition gene panel sequencing (143 genes) were surveyed before and after disclosure of results. Questionnaires assessed knowledge, expectations, worries, satisfaction, and regret. Next to descriptives, linear mixed models and generalized mixed models were utilized to explore factors associated with knowledge and worries.

Results

Out of 325 eligible families, 310 parents (176 mothers and 128 fathers of 188 families) completed all after-consent questionnaires, whereas 260 parents (150 mothers and 110 fathers of 181 families) completed all after disclosure questionnaires. Most parents hoped their participation would benefit others, although individual hopes were also common. Sequencing-related worries were common, particularly concerning whether their child would get cancer again, cancer risks for family members and psychosocial implications of testing. Parental satisfaction after disclosure was high and regret scores were low. Lower education was associated with lower knowledge levels, whereas foreign-born parents were at increased risk of experiencing worries.

Conclusion

Germline sequencing of children with cancer is generally well received by their parents. However, careful genetic counseling is essential to ensure that parents are adequately informed and supported throughout the process.
目的:种系 DNA 测序在儿科肿瘤学中的应用越来越广泛,但对家长的经历却缺乏研究:方法:在结果公布前后,对接受癌症易感基因面板测序(143 个基因)的儿童家长进行了调查。问卷调查内容包括知识、期望、担忧、满意度和遗憾。除描述外,还利用线性混合模型和广义混合模型来探讨与知识和担忧相关的因素:在 325 个符合条件的家庭中,310 名家长(188 个家庭中的 176 名母亲和 128 名父亲)完成了所有同意后问卷,而 260 名家长(181 个家庭中的 150 名母亲和 110 名父亲)完成了所有披露后问卷。大多数家长希望他们的参与能使他人受益,尽管个人希望也很普遍。与序列相关的担忧很常见,尤其是关于孩子是否会再次患癌、家庭成员患癌的风险以及检测对社会心理的影响。披露信息后,家长的满意度较高,后悔得分较低。受教育程度较低与知识水平较低有关,而外国出生的父母出现担忧的风险较高:结论:癌症患儿的种系测序通常会受到家长的欢迎。结论:癌症患儿的基因测序一般都会受到家长的欢迎,但要确保家长在整个过程中获得充分的信息和支持,细致的遗传咨询是必不可少的。
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引用次数: 0
Fraud in genetic testing: Swindling the system 基因检测中的欺诈:诈骗系统。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-03 DOI: 10.1016/j.gim.2024.101248
Rachel Notestine , Claire N. Singletary , Meagan Choates , Stephanie Gandomi , Molly Daniels , Rebecca Lunstroth , Quinn Stein

Purpose

Health care fraud comprises a sizable portion of United States health care expenditure and inflicts undue burden on payors, patients, and the health care system overall. The genetic testing industry is rapidly growing, which propagates opportunities for health care fraud. Although federal organizations have highlighted it as an issue, there is limited research exploring genetic testing fraud.

Methods

A retrospective review of federal websites, news articles, and a legal database resulted in 42 cases of fraud involving outpatient genetic testing published between February 2019 and December 2023. These cases were analyzed for themes via inductive conventional content analysis.

Results

Themes of fraudulent activity included submission of fraudulent claims, kickback or bribe payments, minimal or no contact with patients for whom testing was ordered, inappropriate billing and documentation practices, and further actions to conceal fraud. Repercussions imposed on defendants included monetary penalty, imprisonment, business restrictions, and seizure of property.

Conclusion

High rates of medically inappropriate testing in fraud cases highlight the value of genetics experts in ordering or reviewing claims for genetic testing. Examining fraudulent activity in genetic testing can help providers identify and report fraud and provide awareness of optimal health care allocation in the genetic testing industry.
目的:医疗欺诈占美国医疗支出的很大一部分,给付款人、患者和整个医疗系统造成了不必要的负担。基因检测行业发展迅速,为医疗欺诈提供了可乘之机。尽管联邦机构已将此问题列为重点问题,但有关基因检测欺诈的研究却十分有限:方法:对联邦网站、新闻报道和法律数据库进行回顾性审查,结果发现在 2019 年 2 月至 2023 年 12 月期间发布了 42 起涉及门诊基因检测欺诈的案例。通过归纳式常规内容分析对这些案例进行了主题分析:欺诈活动的主题包括提交虚假索赔、支付回扣或贿赂、极少或根本不与接受检测的患者接触、不恰当的计费和记录做法,以及进一步隐瞒欺诈行为。对被告的处罚包括罚款、监禁、业务限制和没收财产:在欺诈案件中,医疗不当检测的比例很高,这凸显了遗传学专家在开具或审查基因检测索赔时的价值。审查基因检测中的欺诈活动可以帮助医疗服务提供者识别和报告欺诈行为,并为基因检测行业提供最佳医疗分配意识。
{"title":"Fraud in genetic testing: Swindling the system","authors":"Rachel Notestine ,&nbsp;Claire N. Singletary ,&nbsp;Meagan Choates ,&nbsp;Stephanie Gandomi ,&nbsp;Molly Daniels ,&nbsp;Rebecca Lunstroth ,&nbsp;Quinn Stein","doi":"10.1016/j.gim.2024.101248","DOIUrl":"10.1016/j.gim.2024.101248","url":null,"abstract":"<div><h3>Purpose</h3><div>Health care fraud comprises a sizable portion of United States health care expenditure and inflicts undue burden on payors, patients, and the health care system overall. The genetic testing industry is rapidly growing, which propagates opportunities for health care fraud. Although federal organizations have highlighted it as an issue, there is limited research exploring genetic testing fraud.</div></div><div><h3>Methods</h3><div>A retrospective review of federal websites, news articles, and a legal database resulted in 42 cases of fraud involving outpatient genetic testing published between February 2019 and December 2023. These cases were analyzed for themes via inductive conventional content analysis.</div></div><div><h3>Results</h3><div>Themes of fraudulent activity included submission of fraudulent claims, kickback or bribe payments, minimal or no contact with patients for whom testing was ordered, inappropriate billing and documentation practices, and further actions to conceal fraud. Repercussions imposed on defendants included monetary penalty, imprisonment, business restrictions, and seizure of property.</div></div><div><h3>Conclusion</h3><div>High rates of medically inappropriate testing in fraud cases highlight the value of genetics experts in ordering or reviewing claims for genetic testing. Examining fraudulent activity in genetic testing can help providers identify and report fraud and provide awareness of optimal health care allocation in the genetic testing industry.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101248"},"PeriodicalIF":6.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Correspondence on “The Clinical Geneticist Workforce: Community Forums to Address Challenges and Opportunities” by Chung et al 关于 "临床遗传学家队伍:Chung 等人撰写的 "应对挑战和机遇的社区论坛"。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-03 DOI: 10.1016/j.gim.2024.101247
Jennifer Micham , Marshall Summar , Debra Regier , Colleen Lawrence , Deepika Burkardt
{"title":"Correspondence on “The Clinical Geneticist Workforce: Community Forums to Address Challenges and Opportunities” by Chung et al","authors":"Jennifer Micham ,&nbsp;Marshall Summar ,&nbsp;Debra Regier ,&nbsp;Colleen Lawrence ,&nbsp;Deepika Burkardt","doi":"10.1016/j.gim.2024.101247","DOIUrl":"10.1016/j.gim.2024.101247","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101247"},"PeriodicalIF":6.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants 非编码变异是导致隐性发育障碍与编码变异反式的罕见原因。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-03 DOI: 10.1016/j.gim.2024.101249
Jenny Lord , Carolina J. Oquendo , Htoo A. Wai , John G. Holloway , Alexandra Martin-Geary , Alexander J.M. Blakes , Elena Arciero , Silvia Domcke , Anne-Marie Childs , Karen Low , Julia Rankin , Genomics England Research Consortium, Diana Baralle , Hilary C. Martin , Nicola Whiffin

Purpose

Identifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding “second hits” in trans with these is unknown.

Methods

In 4073 genetically undiagnosed rare-disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare noncoding variants on the other haplotype in introns, untranslated regions, promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit and performed functional testing where possible.

Results

We identified 3761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2430 probands. For 1366 (36.3%) of these, we identified at least 1 rare noncoding variant in trans. Bioinformatic filtering and clinical review, revealed 7 to be a good clinical fit. After detailed characterization, we identified likely diagnoses for 3 probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further 3 (PAH, LAMA2, and IGHMBP2).

Conclusion

We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/noncoding variants and conclude that this mechanism is likely to be a rare cause of DDs.
目的:识别致病性非编码变异具有挑战性。在发育障碍(DD)患者的隐性基因中,通常会发现一个改变蛋白质的变异体,但这些变异体中致病性非编码 "二次命中 "的发生率尚不清楚:方法:我们从 100,000 基因组项目中的 4,073 个未确诊罕见病三组探查者中,在隐性 DD 相关基因中发现了罕见的杂合蛋白改变变异。我们在内含子、非翻译区(UTR)、启动子和候选增强子区中发现了另一个单倍型上的罕见非编码变异。我们对最重要的候选基因进行了表型匹配临床评估,并在可能的情况下进行了功能测试:我们在 2430 名受试者的隐性 DD 相关基因中发现了 3761 个罕见的杂合子功能缺失变异或 ClinVar 致病变异。在其中的 1366 例(36.3%)中,我们发现了至少一种罕见的反式非编码变异。通过生物信息学筛选和临床审查,我们发现其中有 7 个临床匹配度较高。经过详细的特征描述,我们确定了三个病例的可能诊断(GAA、NPHP3 和 PKHD1)和另外三个病例的候选诊断(PAH、LAMA2 和 IGHMBP2):我们开发了一种系统方法来发现涉及复合杂合编码/非编码变异的新诊断,并得出结论:这种机制可能是导致 DDs 的罕见原因。
{"title":"Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants","authors":"Jenny Lord ,&nbsp;Carolina J. Oquendo ,&nbsp;Htoo A. Wai ,&nbsp;John G. Holloway ,&nbsp;Alexandra Martin-Geary ,&nbsp;Alexander J.M. Blakes ,&nbsp;Elena Arciero ,&nbsp;Silvia Domcke ,&nbsp;Anne-Marie Childs ,&nbsp;Karen Low ,&nbsp;Julia Rankin ,&nbsp;Genomics England Research Consortium,&nbsp;Diana Baralle ,&nbsp;Hilary C. Martin ,&nbsp;Nicola Whiffin","doi":"10.1016/j.gim.2024.101249","DOIUrl":"10.1016/j.gim.2024.101249","url":null,"abstract":"<div><h3>Purpose</h3><div>Identifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding “second hits” in <em>trans</em> with these is unknown.</div></div><div><h3>Methods</h3><div>In 4073 genetically undiagnosed rare-disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare noncoding variants on the other haplotype in introns, untranslated regions, promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit and performed functional testing where possible.</div></div><div><h3>Results</h3><div>We identified 3761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2430 probands. For 1366 (36.3%) of these, we identified at least 1 rare noncoding variant in trans. Bioinformatic filtering and clinical review, revealed 7 to be a good clinical fit. After detailed characterization, we identified likely diagnoses for 3 probands (in <em>GAA</em>, <em>NPHP3</em>, and <em>PKHD1</em>) and candidate diagnoses in a further 3 (<em>PAH, LAMA2,</em> and <em>IGHMBP2)</em>.</div></div><div><h3>Conclusion</h3><div>We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/noncoding variants and conclude that this mechanism is likely to be a rare cause of DDs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101249"},"PeriodicalIF":6.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
The frequency and clinical impact of synonymous HTT loss-of-interruption and duplication-of-interruption variants in a diverse HD cohort 不同 HD 队列中同义 HTT 缺失中断和重复中断变异的频率和临床影响。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-10 DOI: 10.1016/j.gim.2024.101239
Jessica Dawson , Chris Kay , Hailey Findlay Black , Stephanie Bortnick , Kyla Javier , Qingwen Xia , Akshdeep Sandhu , Christina Buchanan , Virginia Hogg , Florence C.F. Chang , Jun Goto , Larissa Arning , Carsten Saft , Emilia K. Bijlsma , Huu P. Nguyen , Richard Roxburgh , Michael R. Hayden

Purpose

To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD).

Methods

We screened symptomatic HD participants from the UBC HD Biobank and 5 research sites for sequence variants. After variant identification, we examined the clinical impact and frequency in the reduced penetrance range.

Results

Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of Total Motor Score by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of 2 symptomatic HD participants with diagnostic repeats below the pathogenetic range.

Conclusion

Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cutoff ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.

目的:确定亨廷顿病(HD)患者队列中 HTT CAG 和 CCG 重复序列的中断缺失(LOI)和中断重复(DOI)修饰变异的频率及其临床影响:我们对来自 UBC HD 生物库和五个研究机构的有症状 HD 患者进行了序列变异筛选。方法:我们从 UBC HD 生物库和五个研究机构中筛选有症状的 HD 患者,寻找序列变异。在确定变异后,我们研究了变异对临床的影响以及在穿透性降低范围内的频率:结果:具有 CAG-CCG LOI 和 CCG LOI 变体的参与者患 HD 的时间相近,都提前了 12.5 年。序列变异表现出祖先特异性差异。具有 CAG-CCG LOI 变体的患者 TMS 的进展也较快,每年增加 1.9 个单位。有症状的 CAG-CCG LOI 变体参与者在穿透性降低的范围内表现出富集性。CAG-CCG LOI变异可解释两名诊断重复序列低于致病范围的无症状HD患者的发病原因:我们的研究结果对具有 CAG-CCG LOI 变异的参与者具有重要的临床意义,因为他们在诊断临界范围附近得到了不准确的诊断。这些人需要改进诊断测试方法和临床管理。我们展示了最大、最多样化的 HTT CAG 和 CCG 序列变异群,并强调了它们在 HD 临床表现中的重要性。
{"title":"The frequency and clinical impact of synonymous HTT loss-of-interruption and duplication-of-interruption variants in a diverse HD cohort","authors":"Jessica Dawson ,&nbsp;Chris Kay ,&nbsp;Hailey Findlay Black ,&nbsp;Stephanie Bortnick ,&nbsp;Kyla Javier ,&nbsp;Qingwen Xia ,&nbsp;Akshdeep Sandhu ,&nbsp;Christina Buchanan ,&nbsp;Virginia Hogg ,&nbsp;Florence C.F. Chang ,&nbsp;Jun Goto ,&nbsp;Larissa Arning ,&nbsp;Carsten Saft ,&nbsp;Emilia K. Bijlsma ,&nbsp;Huu P. Nguyen ,&nbsp;Richard Roxburgh ,&nbsp;Michael R. Hayden","doi":"10.1016/j.gim.2024.101239","DOIUrl":"10.1016/j.gim.2024.101239","url":null,"abstract":"<div><h3>Purpose</h3><p>To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption modifier variants of the <em>HTT</em> CAG and CCG repeat in a cohort of individuals with Huntington disease (HD).</p></div><div><h3>Methods</h3><p>We screened symptomatic HD participants from the UBC HD Biobank and 5 research sites for sequence variants. After variant identification, we examined the clinical impact and frequency in the reduced penetrance range.</p></div><div><h3>Results</h3><p>Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of Total Motor Score by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of 2 symptomatic HD participants with diagnostic repeats below the pathogenetic range.</p></div><div><h3>Conclusion</h3><p>Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cutoff ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse <em>HTT</em> CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 11","pages":"Article 101239"},"PeriodicalIF":6.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024001734/pdfft?md5=1abcca0080b367715dc410d73f51671a&pid=1-s2.0-S1098360024001734-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for adult screening 测量基因组测序的感知效用:开发并验证用于成人筛查的基因效用(GENE-U)量表。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-10 DOI: 10.1016/j.gim.2024.101240
Hadley Stevens Smith , Caryn Kseniya Rubanovich , Jill Oliver Robinson , Ariel N. Levchenko , Sarah A. Classen , Janet Malek , Adam H. Buchanan , Barbara Biesecker , Kyle B. Brothers , Benjamin S. Wilfond , Christine Rini , Cinnamon S. Bloss , Amy L. McGuire , Sara J. Knight

Purpose

As population-based screening programs to identify genetic conditions in adults using genomic sequencing (GS) are increasingly available, validated patient-centered outcome measures are needed to understand participants’ experience. We aimed to develop and validate an instrument to assess the perceived utility of GS in the context of adult screening.

Methods

Informed by a 5-domain conceptual model, we used a 5-step approach to instrument development and validation: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Adults undergoing risk-based or population-based GS who had received GS results as part of ongoing research studies participated in structured cognitive interviews and 2 rounds of surveys. After item pool refinement, we conducted an exploratory factor analysis and calculated Pearson correlations with related instruments.

Results

We derived the 18-item Adult Screening version of the GENEtic Utility scale (total sum score α = .87). Mirroring the Pediatric Diagnostic version, the instrument has a 2-factor structure, including an Informational Utility subscale (14 items, α = .89) and an Emotional Utility subscale (4 items, α = .75). The Informational Utility subscale was strongly associated with empowerment and personal utility of GS. Correlations of the Emotional Utility subscale with psychosocial impact and anxiety and depression were weak to moderate.

Conclusion

Initial psychometric testing of the Adult Screening GENEtic Utility scale demonstrates its promise, and additional validation in translational genomics research is warranted.

导言:随着使用基因组测序(GS)识别成人遗传病的人群筛查项目越来越多,需要验证以患者为中心的结果测量来了解参与者的体验。我们旨在开发并验证一种工具,以评估成人筛查中对基因测序的感知效用:在五领域概念模型的指导下,我们采用了五步方法来开发和验证工具:(1)项目编写;(2)认知测试;(3)试点测试和项目缩减;(4)心理测试;(5)构建有效性评估。作为正在进行的研究的一部分,正在接受基于风险或基于人群的 GS 并已收到 GS 结果的成年人参加了结构化认知访谈和两轮调查。在完善项目库后,我们进行了探索性因子分析,并计算了与相关工具的皮尔逊相关性:结果:我们得出了18个项目的成人诊断版基因效用量表(GENE-U)(总分α = .87)。与儿科诊断版本相同,该量表具有双因子结构,包括信息效用子量表(14 个项目,α = 0.89)和情感效用子量表(4 个项目,α = 0.75)。信息效用分量表与 GS 的授权和个人效用密切相关。情感效用子量表与心理社会影响、焦虑和抑郁的相关性为弱至中等:成人筛查 GENE-U 量表的初步心理测试表明了它的前景,有必要在转化基因组学研究中进行进一步验证。
{"title":"Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for adult screening","authors":"Hadley Stevens Smith ,&nbsp;Caryn Kseniya Rubanovich ,&nbsp;Jill Oliver Robinson ,&nbsp;Ariel N. Levchenko ,&nbsp;Sarah A. Classen ,&nbsp;Janet Malek ,&nbsp;Adam H. Buchanan ,&nbsp;Barbara Biesecker ,&nbsp;Kyle B. Brothers ,&nbsp;Benjamin S. Wilfond ,&nbsp;Christine Rini ,&nbsp;Cinnamon S. Bloss ,&nbsp;Amy L. McGuire ,&nbsp;Sara J. Knight","doi":"10.1016/j.gim.2024.101240","DOIUrl":"10.1016/j.gim.2024.101240","url":null,"abstract":"<div><h3>Purpose</h3><p>As population-based screening programs to identify genetic conditions in adults using genomic sequencing (GS) are increasingly available, validated patient-centered outcome measures are needed to understand participants’ experience. We aimed to develop and validate an instrument to assess the perceived utility of GS in the context of adult screening.</p></div><div><h3>Methods</h3><p>Informed by a 5-domain conceptual model, we used a 5-step approach to instrument development and validation: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Adults undergoing risk-based or population-based GS who had received GS results as part of ongoing research studies participated in structured cognitive interviews and 2 rounds of surveys. After item pool refinement, we conducted an exploratory factor analysis and calculated Pearson correlations with related instruments.</p></div><div><h3>Results</h3><p>We derived the 18-item Adult Screening version of the GENEtic Utility scale (total sum score α = .87). Mirroring the Pediatric Diagnostic version, the instrument has a 2-factor structure, including an Informational Utility subscale (14 items, <span><math><mrow><mi>α</mi></mrow></math></span> = .89) and an Emotional Utility subscale (4 items, <span><math><mrow><mi>α</mi></mrow></math></span> = .75). The Informational Utility subscale was strongly associated with empowerment and personal utility of GS. Correlations of the Emotional Utility subscale with psychosocial impact and anxiety and depression were weak to moderate.</p></div><div><h3>Conclusion</h3><p>Initial psychometric testing of the Adult Screening GENEtic Utility scale demonstrates its promise, and additional validation in translational genomics research is warranted.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 11","pages":"Article 101240"},"PeriodicalIF":6.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules LZTR1功能缺失变异的杂合子与孤立的多发性咖啡色黄斑有关。
IF 6.6 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-10 DOI: 10.1016/j.gim.2024.101241
Gioia Mastromoro , Claudia Santoro , Marialetizia Motta , Ugo Sorrentino , Paola Daniele , Cristina Peduto , Francesco Petrizzelli , Martina Tripodi , Valentina Pinna , Mariateresa Zanobio , Giovannina Rotundo , Emanuele Bellacchio , Francesca Lepri , Antonella Farina , Maria Cecilia D’Asdia , Francesca Piceci-Sparascio , Tommaso Biagini , Antonio Petracca , Marco Castori , Daniela Melis , Alessandro De Luca

Purpose

Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs).

Methods

A total of 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions.

Results

Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated but occasionally associated with features recurring in RASopathies. In 2 families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating loss-of-function. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate mitogen-activated protein kinase signaling.

Conclusion

Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.
目的:致病性 LZTR1 变异可导致分裂瘤病和显性/隐性努南综合征(NS)。我们旨在确定杂合性功能缺失(LoF)LZTR1 等位基因与孤立性多发性咖啡色斑疹(CaLMs)之间的关联。方法:849 名患有多发性 CaLMs、缺乏致病性/可能致病性 NF1 和 SPRED1 变体的非亲属参与者接受了 RASopathy 基因面板测序。收集了125名LZTR1杂合子变异者的数据,以确定其临床特征和相关的分子谱。对具有代表性的错义变异和小框架内缺失进行了体外功能评估:结果:分析显示,6.0%(51/849)的参与者存在杂合 LZTR1 变异,超过了一般人群的患病率。与LZTR1相关的CaLM数量不等,边界清晰或不规则,通常是孤立的,但偶尔与RAS病中复发的特征相关。在两个家族中,CaLMs 和精神分裂症同时出现。分子谱主要包括截短变异,表明存在 LoF。这些变异与发生在分裂瘤病和隐性 NS 中的变异基本重叠。功能表征显示蛋白质降解加速或定位错误,以及不能下调 MAPK 信号转导:我们的研究结果扩大了与 LZTR1 变异相关的表型变异性,LZTR1 变异除了易感于分裂瘤病并导致显性和隐性 NS 外,还出现在孤立的多 CaLMs 患者中。
{"title":"Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules","authors":"Gioia Mastromoro ,&nbsp;Claudia Santoro ,&nbsp;Marialetizia Motta ,&nbsp;Ugo Sorrentino ,&nbsp;Paola Daniele ,&nbsp;Cristina Peduto ,&nbsp;Francesco Petrizzelli ,&nbsp;Martina Tripodi ,&nbsp;Valentina Pinna ,&nbsp;Mariateresa Zanobio ,&nbsp;Giovannina Rotundo ,&nbsp;Emanuele Bellacchio ,&nbsp;Francesca Lepri ,&nbsp;Antonella Farina ,&nbsp;Maria Cecilia D’Asdia ,&nbsp;Francesca Piceci-Sparascio ,&nbsp;Tommaso Biagini ,&nbsp;Antonio Petracca ,&nbsp;Marco Castori ,&nbsp;Daniela Melis ,&nbsp;Alessandro De Luca","doi":"10.1016/j.gim.2024.101241","DOIUrl":"10.1016/j.gim.2024.101241","url":null,"abstract":"<div><h3>Purpose</h3><div>Pathogenic <em>LZTR1</em> variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function <em>LZTR1</em> alleles and isolated multiple café-au-lait macules (CaLMs).</div></div><div><h3>Methods</h3><div>A total of 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic <em>NF1</em> and <em>SPRED1</em> variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous <em>LZTR1</em> variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions.</div></div><div><h3>Results</h3><div>Analysis revealed heterozygous <em>LZTR1</em> variants in 6.0% (51/849) of participants, exceeding the general population prevalence. <em>LZTR1</em>-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated but occasionally associated with features recurring in RASopathies. In 2 families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating loss-of-function. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate mitogen-activated protein kinase signaling.</div></div><div><h3>Conclusion</h3><div>Our findings expand the phenotypic variability associated with <em>LZTR1</em> variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 11","pages":"Article 101241"},"PeriodicalIF":6.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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Genetics in Medicine
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