Orphanet Journal of Rare Diseases | First Report of Neonatal-Onset Glutaric Aciduria Type II Caused by a Novel ETFA Mutation

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This study reports for the first time a neonatal-onset case of glutaric aciduria type II (GA2) caused by a novel ETFA gene mutation in the Iranian population, highlighting the heterogeneous clinical manifestations of GA2 and the importance of whole exome sequencing in diagnosing rare metabolic disorders.

 

Literature Overview
This article, entitled 'First Report of Neonatal-Onset Glutaric Aciduria Type II in the Iranian Population Caused by a Novel ETFA Mutation', published in the Orphanet Journal of Rare Diseases, reviews and summarizes the clinical features and genetic mutations of GA2, and for the first time identifies a neonatal-onset GA2 case caused by a novel ETFA gene mutation in the Iranian population. The mutation was identified through whole exome sequencing (WES) and Sanger sequencing, and a novel heterozygous deletion variant c.485_493del: p.E162_T164del in the ETFA gene was analyzed for pathogenicity using bioinformatics tools. This study further supports the critical role of WES in the diagnosis of heterogeneous inherited metabolic disorders.

Background Information
Glutaric Aciduria Type II (GA2), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is an autosomal recessive metabolic disorder caused by mutations in the ETFA, ETFB, or ETFDH genes. It primarily affects fatty acid β-oxidation and amino acid metabolism, leading to severe metabolic disturbances such as hypoglycemia, metabolic acidosis, and hyperammonemia. The clinical presentation of GA2 is highly heterogeneous, ranging from life-threatening metabolic crises in the neonatal period to adult-onset myopathy, making diagnosis and treatment challenging. Current research focuses on genotype-phenotype correlations, optimization of prenatal diagnostic techniques, and the efficacy of nutritional and coenzyme supplementation therapies. This study represents the first report of ETFA-related GA2 in the Iranian population, filling a gap in regional genetic research and providing new insights for prenatal screening and genetic counseling.

 

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Research Methods and Experiments
The research team conducted prenatal diagnosis and genetic counseling for an Iranian family from the Semnan province. The couple had lost two newborns (III.1 and III.2) to suspected metabolic disorders and had a history of consanguineous marriage. Whole exome sequencing (WES) was performed on the parents, and the identified variant was confirmed using Sanger sequencing. Bioinformatics tools (such as Mutation Taster, Varsome, Phyre2, NetSurfP-2.0, ClustalW) were used to evaluate the impact of the mutation on the structure and function of the ETFA protein. Prenatal diagnosis was carried out on the fetus (III.4), and pregnancy was terminated based on the genetic findings.

Key Findings and Insights

• A novel ETFA deletion variant c.485_493del: p.E162_T164del was identified, marking the first report in the Iranian population.
• This variant lies within exon 6 of the ETFA gene, encoding three highly conserved amino acids (E, L, T) in the C-terminal domain, indicating its importance for protein function.
• Bioinformatics analysis suggests this mutation causes conformational changes in the ETF-C functional domain, impairing FAD cofactor binding and leading to loss of ETFA protein function.
• The mutation follows an autosomal recessive pattern, with both parents as carriers and the fetus being homozygous for the mutation.
• This study highlights the diagnostic value of WES in heterogeneous metabolic disorders and provides a molecular basis for future genetic counseling and prenatal screening.
• The clinical phenotype associated with this mutation is consistent with global GA2 cases, including severe hypoglycemia, hyperammonemia, metabolic acidosis, and cardiac abnormalities.

Significance and Future Directions
This study is the first to identify an ETFA mutation causing GA2 in the Iranian population, offering new genetic evidence for the molecular mechanisms of the disease and underscoring the importance of early genetic screening and prenatal diagnosis in high-risk families. Future studies may focus on functional characterization of this mutation and its carrier frequency across populations to improve genetic counseling and disease management strategies.

 

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Conclusion
This study reports the first identification of a novel ETFA mutation c.485_493del: p.E162_T164del in the Iranian population, confirmed to be pathogenic for glutaric aciduria type II (GA2). The mutation causes the deletion of three highly conserved amino acids, affecting the C-terminal domain and FAD binding of the ETFA protein, ultimately leading to loss of function. The study further confirms the crucial role of whole exome sequencing in diagnosing rare metabolic diseases and provides a new molecular basis for prenatal screening and genetic counseling. This research not only expands the spectrum of known ETFA mutations but also emphasizes the necessity of systematic molecular diagnostics for rare genetic disorders, especially in populations with high rates of consanguineous marriages.

 

Farshid Parvini, Mobarakeh Ajam-Hosseini, and Marziyeh Shadpour. First report of neonatal-onset glutaric aciduria type II in the Iranian population caused by a novel deleterious ETFA variant. Orphanet Journal of Rare Diseases.