Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency

Area of Science:

• Genetics
• Metabolic Disorders
• Molecular Biology

Background:

• Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inherited metabolic disorder affecting fatty acid and amino acid oxidation.
• It presents with diverse phenotypes, from severe neonatal onset to milder late-onset forms, diagnosed via biochemical analyses.
• Genetic basis involves mutations in ETFA, ETFB, and ETFDH genes, but some patients remain undiagnosed.

Observation:

• Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) enabled definitive molecular diagnosis in a newborn with MADD.
• Standard methods like whole-exome sequencing and gene panels missed a deep intronic variant.
• A novel deep intronic mutation (c.35-959A>G) in ETFDH intron 1 was identified, causing pseudo-exon inclusion and lethal MADD.

Findings:

• The study identified a unique deep intronic mutation in the ETFDH gene (c.35-959A>G) responsible for a severe MADD case.
• This mutation leads to the inclusion of a pseudo-exon, disrupting normal gene function.
• ETFDH intron 1 appears vulnerable to mutations, with this being the third reported in this specific region.

Implications:

• Integrating RNA sequencing with WGS is crucial for diagnosing genetic disorders caused by intronic variants.
• This approach can improve diagnostic yield for MADD and potentially other inherited diseases.
• Understanding intronic mutation mechanisms broadens the scope of genetic diagnostics and counseling.