Identification of Two Siblings with PMM2-Congenital Disorder of Glycosylation Using Exome Sequencing in South East of Iran: Clinical and Genetic Findings

Abstract

Background: Congenital disorders of glycosylation (CDG) encompass a broad spectrum of rare inborn errors of metabolism (IEMs), resulting in defective glycosylation of various proteins and/or lipids. PMM2-CDG is the most prevalent subtype of CDG, characterized by gene mutations leading to deficiency of the phosphomannomutase 2 (PMM2) enzyme. This research identified two Iranian patients from a consanguineous family with multiple organ dysfunctions, diagnosed with PMM2-CDG due to a pathogenic variant in the PMM2 gene. The study underscores the importance of identifying specific variants in different ethnic groups for effective genetic counseling for this disorder. Methods: The study utilized exome sequencing (ES) to identify pathogenic variants. Verification of the potential variant in affected siblings, along with segregation analysis involving the parents, affected individuals, and healthy siblings of the family, was performed using Sanger sequencing. Interpretation of the variant was informed by multiple in silico analysis tools, as well as by adhering to the guidelines set forth by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). Results: In the genomic investigations of the two brothers with intellectual disability (ID) and progressive movement disability, the NM_000303.3:c.647A > T (NP_000294.1:p.Asn216Ile) homozygous variant in the PMM2 gene was identified. The variant was confirmed in the affected and other family members by segregation analysis. Multiple in silico tools supported the pathogenic classification of the identified variant. Conclusions: The findings provide broader insight into variants within the PMM2 gene and offer a thorough characterization of the phenotype related to this specific variant. The data have important applications for genetic diagnosis and counseling in relevant clinical contexts, as well as for identifying common gene variants associated with various ethnic groups. Additionally, this information could serve as a valuable resource in guiding therapeutic interventions.