Whole exome sequencing identifies a novel variant causing Neurodegeneration with Brain Iron Accumulation syndrome (NBIA) in a consanguineous Pashtun family.

Neurodegenerative disorders pose a significant public health problem. Among these, neurodegeneration with brain iron accumulation syndrome (NBIA) is particularly challenging because even MRI imaging findings can be subtle. Understanding the genetic basis of NBIA is, therefore, crucial for early diagnosis. This study aims to identify pathogenic mutations underlying NBIA in a consanguineous Pashtun family from Pakistan, using Next Generation Sequencing and protein structure modeling. Whole exome sequencing identified a novel pathogenic variant segregating in the family. Bioinformatics tools were employed for assessing the pathogenicity of the variant and 3D structure modelling of the protein. Following the filtration of variants according to the pedigree structure, we identified a novel homozygous variant (NM_001286611.1:c.1460A > C, p.Lys487Thr) in the REPS1 gene in the proband. Subsequent analysis confirmed the segregation of this variant within the family. Identification of this mutation expands our understanding of NBIA genetics and aids in early diagnosis. Stabilizing energy calculations support the impact of this variant on normal portion functioning.