Optical genome mapping reveals maternal mosaicism in two Sibling cases of Early-Onset Facioscapulohumeral muscular dystrophy type 1

IF 3.2 3区医学 Q2 MEDICAL LABORATORY TECHNOLOGY

Clinica Chimica Acta Pub Date : 2024-11-26 DOI:10.1016/j.cca.2024.120062

Chen Liu , Rui Dong , Bingyi Shi , Kai Ma , Lili Kang , Xiaomei Li , Xianghong Liu , Lili Miao , Huiting Yu , Yuqiang Lv , Haiyan Zhang , Xiaoying Li

{"title":"Optical genome mapping reveals maternal mosaicism in two Sibling cases of Early-Onset Facioscapulohumeral muscular dystrophy type 1","authors":"Chen Liu , Rui Dong , Bingyi Shi , Kai Ma , Lili Kang , Xiaomei Li , Xianghong Liu , Lili Miao , Huiting Yu , Yuqiang Lv , Haiyan Zhang , Xiaoying Li","doi":"10.1016/j.cca.2024.120062","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant condition caused by shortened D4Z4 repeat units in the subtelomeric region of 4q35, always on the 4qA haplotype, or due to variants in the <em>SMCHD1</em> gene leading to hypomethylation of the D4Z4 macrosatellite DNA repeats.</div></div><div><h3>Methods</h3><div>To explore the potential genetic basis for suspected FSHD presenting with early onset in two siblings without evident family history of the disorder, whole genome sequencing (WGS) and optical genome mapping (OGM) were conducted on the affected individuals and their parents.</div></div><div><h3>Results</h3><div>The two siblings manifested severe and early-onset clinical features consistent with FSHD, initiating with facial muscle weakness that progressively spread downward since the age of four months. OGM disclosed a reduced number of D4Z4 repeat units within the subtelomeric region of 4q35 in both affected siblings. This finding was pivotal in establishing the diagnosis of FSHD1 in the two brothers. The analysis also revealed that their clinically asymptomatic mother harbored the pathogenic D4Z4 repeat configuration (4qA) at a 50% frequency, indicating her mosaic carrier status. Additionally, WGS and Sanger sequencing identified a paternal origin variant c.695_699del (p.Val232Glyfs*7) in the <em>DNAJB6</em> gene in both siblings.</div></div><div><h3>Conclusion</h3><div>The application of advanced genomic methodologies has proven instrumental in unraveling the intricacies of genetic diseases that challenge traditional diagnostic paradigms. Specifically, this study highlights the effectiveness of OGM in diagnosing FSHD1 and confirming D4Z4 repeat reduction, particularly in cases involving parental mosaicism.</div></div>","PeriodicalId":10205,"journal":{"name":"Clinica Chimica Acta","volume":"566 ","pages":"Article 120062"},"PeriodicalIF":3.2000,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinica Chimica Acta","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0009898124023155","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICAL LABORATORY TECHNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant condition caused by shortened D4Z4 repeat units in the subtelomeric region of 4q35, always on the 4qA haplotype, or due to variants in the SMCHD1 gene leading to hypomethylation of the D4Z4 macrosatellite DNA repeats.

Methods

To explore the potential genetic basis for suspected FSHD presenting with early onset in two siblings without evident family history of the disorder, whole genome sequencing (WGS) and optical genome mapping (OGM) were conducted on the affected individuals and their parents.

Results

The two siblings manifested severe and early-onset clinical features consistent with FSHD, initiating with facial muscle weakness that progressively spread downward since the age of four months. OGM disclosed a reduced number of D4Z4 repeat units within the subtelomeric region of 4q35 in both affected siblings. This finding was pivotal in establishing the diagnosis of FSHD1 in the two brothers. The analysis also revealed that their clinically asymptomatic mother harbored the pathogenic D4Z4 repeat configuration (4qA) at a 50% frequency, indicating her mosaic carrier status. Additionally, WGS and Sanger sequencing identified a paternal origin variant c.695_699del (p.Val232Glyfs*7) in the DNAJB6 gene in both siblings.

Conclusion

The application of advanced genomic methodologies has proven instrumental in unraveling the intricacies of genetic diseases that challenge traditional diagnostic paradigms. Specifically, this study highlights the effectiveness of OGM in diagnosing FSHD1 and confirming D4Z4 repeat reduction, particularly in cases involving parental mosaicism.

查看原文本刊更多论文

光学基因组图谱揭示了两例早发面胛肱肌营养不良症1型同胞的母体嵌合。

背景：面岬-肱肌营养不良症（FSHD）是一种常染色体显性遗传病，其病因是4q35亚群区的D4Z4重复单位变短，总是位于4qA单倍型上，或者是由于SMCHD1基因的变异导致D4Z4大卫星DNA重复单位的低甲基化：为了探究无明显家族病史的两兄妹早发性疑似前列腺增生症的潜在遗传基础，我们对患者及其父母进行了全基因组测序（WGS）和光学基因组图谱绘制（OGM）：结果：这对兄妹表现出与FSHD一致的严重早发临床特征，从4个月大开始面部肌肉无力，并逐渐向下扩散。OGM发现两兄妹的4q35亚群中D4Z4重复单位数量减少。这一发现对确诊两兄弟患有 FSHD1 起了关键作用。分析还发现，他们临床上无症状的母亲携带致病的D4Z4重复单位（4qA）的频率为50%，这表明她是马赛克携带者。此外，WGS 和 Sanger 测序还在两兄妹的 DNAJB6 基因中发现了父源变异 c.695_699del（p.Val232Glyfs*7）：事实证明，先进基因组学方法的应用有助于揭开遗传疾病的神秘面纱，对传统诊断模式提出了挑战。本研究特别强调了 OGM 在诊断 FSHD1 和确认 D4Z4 重复减少方面的有效性，尤其是在涉及父母嵌合的病例中。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Clinica Chimica Acta 医学-医学实验技术

CiteScore

10.10

自引率

2.00%

发文量

1268

审稿时长

23 days

期刊介绍： The Official Journal of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Clinica Chimica Acta is a high-quality journal which publishes original Research Communications in the field of clinical chemistry and laboratory medicine, defined as the diagnostic application of chemistry, biochemistry, immunochemistry, biochemical aspects of hematology, toxicology, and molecular biology to the study of human disease in body fluids and cells. The objective of the journal is to publish novel information leading to a better understanding of biological mechanisms of human diseases, their prevention, diagnosis, and patient management. Reports of an applied clinical character are also welcome. Papers concerned with normal metabolic processes or with constituents of normal cells or body fluids, such as reports of experimental or clinical studies in animals, are only considered when they are clearly and directly relevant to human disease. Evaluation of commercial products have a low priority for publication, unless they are novel or represent a technological breakthrough. Studies dealing with effects of drugs and natural products and studies dealing with the redox status in various diseases are not within the journal''s scope. Development and evaluation of novel analytical methodologies where applicable to diagnostic clinical chemistry and laboratory medicine, including point-of-care testing, and topics on laboratory management and informatics will also be considered. Studies focused on emerging diagnostic technologies and (big) data analysis procedures including digitalization, mobile Health, and artificial Intelligence applied to Laboratory Medicine are also of interest.