Jang Joowon, Sung Hobin, Lee Jung-Ae, Cho Sung Im, Lee Jee-Soo, Seong Moon-Woo
Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, The Republic of Korea.
Biomedical Research Institute, Seoul National University Hospital, Seoul, The Republic of Korea.
J Med Genet. 2025 Jun 24;62(7):467-475. doi: 10.1136/jmg-2024-110382.
Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder caused by contraction or hypomethylation of the D4Z4 repeat array located at chromosome 4q35. For the disease to manifest, a permissive haplotype is required, as it enables the pathogenic expression of the gene. FSHD cases often involve complex rearrangements, such as intrachromosomal rearrangements and translocations, which complicate diagnosis using conventional methods. This study focuses on evaluating the diagnostic potential of single molecule optical mapping (SMOM) for FSHD with complex rearrangements, particularly in cases involving 4q-10q translocations, which present challenges for detection by SMOM alone. Furthermore, we propose an integrated diagnostic strategy, combining SMOM with complementary methods, to improve accuracy in these challenging cases.
We reviewed the test results of 238 patients with suspected FSHD, and 25 participants with presumed complex rearrangements were included in this study. SMOM was performed on these participants, and the results were manually reviewed and compared with those obtained from Southern blot (SB) analysis.
Nine patients carrying 4q-10q translocation exhibited discrepancies between the two methods. Linear regression analysis revealed a significant discrepancy in chromosomal assignment between SB and SMOM in cases suspected of translocation.
Given the complex nature of FSHD, none of the current methods can independently provide a definitive diagnosis. As misdiagnosis may occur when relying on a single technique, we propose an integrated diagnostic approach, with SMOM as the first-line test.
面肩肱型肌营养不良症（FSHD）是一种由位于染色体4q35的D4Z4重复序列收缩或低甲基化引起的遗传性疾病。该疾病的发生需要一个许可单倍型，因为它能使致病基因得以表达。FSHD病例常涉及复杂的重排，如染色体内重排和易位，这使得使用传统方法进行诊断变得复杂。本研究重点评估单分子光学图谱（SMOM）对伴有复杂重排的FSHD的诊断潜力，特别是在涉及4q-10q易位的病例中，仅靠SMOM检测存在挑战。此外，我们提出一种综合诊断策略，将SMOM与补充方法相结合，以提高这些具有挑战性病例的诊断准确性。
我们回顾了238例疑似FSHD患者的检测结果，本研究纳入了25例推测有复杂重排的参与者。对这些参与者进行了SMOM检测，并对结果进行人工审核，与Southern印迹（SB）分析结果进行比较。
9例携带4q-10q易位的患者在两种方法之间表现出差异。线性回归分析显示，在疑似易位的病例中，SB和SMOM在染色体定位上存在显著差异。
鉴于FSHD的复杂性，目前没有一种方法能够独立提供明确的诊断。由于仅依靠单一技术可能会发生误诊，我们提出一种综合诊断方法，以SMOM作为一线检测方法。
