Exploring Baralle-Macken Syndrome: A Novel COPB1 Mutation in Consanguineous Pakistani Siblings

Monogenic neurological disorders significantly contribute to global morbidity and mortality, yet their genetic mechanisms remain poorly understood, especially in consanguineous Pakistani populations with over 83% consanguinity rates. The underrepresentation of these populations in global genomic databases complicates the interpretation of rare genetic variants crucial for diagnostics and healthcare outcomes. Baralle-Macken syndrome (BARMACS) is a rare autosomal recessive disorder caused by mutations in the COPB1 gene, essential for transporting proteins and lipids within cellular compartments, including neurons. While only two homozygous COPB1 mutations have been previously reported, we describe a third novel variant (Chr11(GRCh37): g.14480187C>A; NM_016451.4: c.2693G>T; p.Arg898Leu) identified in two male siblings from a consanguineous Pakistani family. This variant alters a highly conserved arginine residue, suggesting a pathogenic effect on protein function, potentially disrupting transport between the Golgi apparatus and the endoplasmic reticulum and impairing early brain development. Our study marks the first report of Baralle-Macken syndrome in a Pakistani population, highlighting a novel missense mutation in COPB1 associated with the disorder, and represents the first documented case involving affected males. These findings emphasize the necessity for further investigation into the functional consequences of COPB1 mutations and their impact on disease pathology.