From Screening to Diagnosis: ACADSB Variant Co-Inheritance Causing ۲-Methylbutyrylglycinuria in an Iranian Neonate

Short/branched-chain acyl-CoA dehydrogenase deficiency, also known as ۲-methylbutyrylglycinuria, is a rare autosomal recessive metabolic disorder affecting the catabolism of L-isoleucine. Early detection through newborn screening programs using tandem mass spectrometry enables timely diagnosis and intervention, potentially preventing severe clinical outcomes. In this study, we report a case identified through Iran's national newborn screening program, presenting with elevated C۵-acylcarnitine levels. Whole exome sequencing revealed compound heterozygosity for two ACADSB gene variants: c.۹۰۸G>C and c.۱۱۵۹G>A. While c.۱۱۵۹G>A is classified as pathogenic, c.۹۰۸G>C was previously considered a variant of uncertain significance. However, the observed biochemical phenotype and in silico analysis support reclassification of c.۹۰۸G>C as likely pathogenic. This case highlights the importance of integrating genotype–phenotype correlation and advanced genomic tools to refine variant interpretation and improve diagnostic accuracy in rare metabolic disorders.

کلیدواژه ها:

ACADSB gene ، Newborn screening ، ۲-methylbutyrylglycinuria