Identification and In Silico Analysis of a Novel Mutation of MAN2B1 Gene in Congenital Family with Alpha-Mannosidosis from Pakistan

Alpha-mannosidosis is a devastating metabolic disorder characterized by intellectual disability, facial dysmorphism, musculoskeletal and immune abnormalities. This study identifies a genetic mutation in a complex consanguineous Pakistani family of Punjabi language group. The family presented with rare complex neurological symptoms including mental retardation, facial dysmorphism, skeletal and muscle abnormalities. Five affected family members were recruited along with unaffected members, and whole blood was collected for genomic DNA extraction. A genome-wide scan was carried out on four affected members to establish homozygosity linkage. The analysis for genotype assessment was carried out, and three homozygous regions were identified. Whole exome sequencing was carried out to identify themutation in putative gene/s. The data was arranged, and MAN2B1 was selected for the DNA sequencing.Protein homology was analyzed by the pymol tool to predict the effect on the mutant protein. A novelmissense mutation c. 2710A>T; p.904Tyr>Ser was detected, and co-segregation analysis was establishedin the complex neurological family. The pymol analysis detected the loss of hydrogen bonding betweenThr at 904 with Arg at 916 in mutant MAN2B1. It is concluded that a novel mutation is identified inMAN2B1 associated with a complex neurological disease. The results indicate huge heterogeneity in thePakistani population due to consanguinity. The combination of next-generation sequencing has facilitated the identification of genes in complex disorders like alpha-mannosidosis.