Deep intronic variants: a neglected diagnostic blind spot in genetic testing for inherited skeletal muscle diseases
10.3760/cma.j.cn113694-20250729-00442
- VernacularTitle:深度内含子变异：遗传性骨骼肌疾病基因检测中不可忽视的诊断盲区
- Author:
Pengfei LIN
1
;
Chuanzhu YAN
1
Author Information
1. 山东大学齐鲁医院神经内科 山东省罕见病线粒体医学重点实验室，济南250012
- Publication Type:Journal Article
- Keywords:
Deep intronic variants;
Inherited skeletal muscle diseases;
Whole genome sequencing
- From:
Chinese Journal of Neurology
2025;58(12):1245-1249
- CountryChina
- Language:Chinese
-
Abstract:
Deep intronic variants refer to genetic variants located within intronic regions that are more than 100 base pairs away from exon-intron boundaries. These variants have historically been overlooked in the genetic testing of hereditary skeletal muscle diseases. Conventional genetic testing methods, such as whole exome sequencing, primarily focus on coding regions and exon-intron junctions [±(50-200) bp], thereby failing to detect abnormalities in extensive intronic regions. Furthermore, assessing the pathogenicity of identified deep intronic variants remains challenging. Recent studies have demonstrated that certain hereditary myopathies can be attributed to deep intronic variants. The underlying pathogenic mechanisms include the formation of pseudoexons, activation of cryptic splice sites, and disruption of transcriptional regulation. Although deep intronic variants can be detected using whole-genome sequencing or third-generation long-read sequencing technologies, these approaches are associated with high costs and difficulties in interpreting the results. Clinically, a combination of multiple detection methods is necessary for comprehensive analysis. Integrating functional validation techniques, such as RNA sequencing and minigene assays, facilitates the interpretation of deep intronic variants and enhances diagnostic yield, thereby offering novel insights into the diagnosis and management of hereditary myopathies.
