Liu Chen, Dong Rui, Shi Bingyi, Ma Kai, Kang Lili, Li Xiaomei, Liu Xianghong, Miao Lili, Yu Huiting, Lv Yuqiang, Zhang Haiyan, Li Xiaoying
Neonatology Department, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China; Shandong Provincial Clinical Research Center for Children's Health and Disease, Jinan, China.
Shandong Provincial Clinical Research Center for Children's Health and Disease, Jinan, China; Pediatric Research Institute, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China.
Clin Chim Acta. 2025 Jan 30;566:120062. doi: 10.1016/j.cca.2024.120062. Epub 2024 Nov 26.
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.
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.
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.
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.
面肩肱型肌营养不良症（FSHD）是一种常染色体显性疾病，由4q35亚端粒区域的D4Z4重复单元缩短引起，通常位于4qA单倍型上，或者是由于SMCHD1基因的变异导致D4Z4大卫星DNA重复序列的低甲基化。
为了探究两名无明显该疾病家族史但疑似早发型FSHD的兄弟姐妹潜在的遗传基础，对患病个体及其父母进行了全基因组测序（WGS）和光学基因组图谱分析（OGM）。
这两名兄弟姐妹表现出与FSHD一致的严重早发临床特征，自四个月大时起从面部肌肉无力开始，逐渐向下蔓延。OGM显示，两名患病兄弟姐妹的4q35亚端粒区域内的D4Z4重复单元数量减少。这一发现对于确诊这两名兄弟的FSHD1至关重要。分析还显示，他们临床无症状的母亲携带致病D4Z4重复构型（4qA）的频率为50%，表明她是嵌合携带者状态。此外，WGS和桑格测序在两名兄弟姐妹的DNAJB6基因中均鉴定出一个来自父亲的变异c.695_699del（p.Val232Glyfs*7）。
先进基因组方法的应用已被证明有助于揭示挑战传统诊断模式的遗传疾病的复杂性。具体而言，本研究突出了OGM在诊断FSHD1和确认D4Z4重复序列减少方面的有效性，特别是在涉及父母嵌合现象的病例中。
