Genotype-Phenotype Correlation of ETF Dehydrogenase Gene-Related Multiple Acyl-CoA Dehydrogenation Deficiency in Chinese Patients

• Published in: The FASEB journal Vol. 39; no. 16; p. e70960
• Main Authors: Liang, Hui, Ye, Ziling, Yang, Lin, Liu, Yue, Lin, Minting, Wang, Zhiqiang, Liu, Xinyi, Chen, Wan-Jin, Yang, Kang
• Format: Journal Article
• Language: English
• Published: United States 31.08.2025
• Subjects: Adolescent; Adult; Child; Child, Preschool; China - ethnology; East Asian People - ethnology; East Asian People - genetics; Electron-Transferring Flavoproteins - genetics; Female; Genetic Association Studies; Genotype; Humans; Infant; Iron-Sulfur Proteins - genetics; Male; Multiple Acyl Coenzyme A Dehydrogenase Deficiency - genetics; Multiple Acyl Coenzyme A Dehydrogenase Deficiency - pathology; Mutation; Mutation, Missense; Oxidoreductases Acting on CH-NH Group Donors - genetics; Phenotype; Young Adult; China
• ISSN: 1530-6860
• DOI: 10.1096/fj.202500779RR

Multiple Acyl-CoA dehydrogenation deficiency (MADD) is an autosomal recessive inherited disease characterized by myopathic manifestation linked to fatty acid oxidation. The ETF dehydrogenase (ETFDH) gene is the most common gene associated with MADD. This study summarizes the clinical and genetic characteristics of 422 Chinese patients with ETFDH gene-related MADD. We analyzed the clinical features, pathological characteristics, and genetic profiles of 30 ETFDH gene-related MADD patients from our hospital and reviewed the clinical and mutational profiles of 392 previously reported Chinese patients. Patients were grouped based on mutation locations to analyze genotype-phenotype correlations. A total of 169 ETFDH mutations were identified, with missense mutation (70.4%) being the most common type. The most frequent mutations in the Chinese population were A84T, Y257C, and L409F, accounting for 19.9%, 10.5%, and 6% of total alleles, respectively. Patients carrying A84T had an earlier onset age by 10 years compared to other patients, while those with Y257C had a later onset age by 8 years. In the FAD-binding domain group, females had a significantly earlier onset than males (p < 0.05), while in the UQ-binding domain/NULL group, males had an earlier onset than females (p < 0.05). The A84T mutation is the most common ETFDH variant in China. Patients with A84T mutations experience earlier onset, while those with Y257C mutations have a later onset age. These findings highlight the importance of genotype-phenotype correlations in ETFDH-related MADD and emphasize the need for larger cohorts and functional studies to elucidate the impact of specific mutations.