MAN2B2

Inheritance Pattern: AR

Disease ID:MONDO:0015286

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0800141

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0800141

Submitter: ClinGen

MAN2B2 was first reported in relation to autosomal recessive inheritance of MAN2B2 Deficiency, a type of Congenital Disorders of Glycosylation (CDG) in 2020 (Verheijen et al., PMID: 31775018). There are many subtypes of CDGs, and they affect a broad range of glycosylation pathways: MAN2B2 deficiency CDG is characterized by abnormal N-glycosylation and monosaccharide activation. There are only 2 known affected individuals and they have a broad range of phenotypes (Verheijen et al., PMID: 31775018) and (Tian et al. PMID:35637269). One individual has combined immunodeficiency, but both have developmental delays (Verheijen et al., PMID: 31775018) and (Tian et al. PMID:35637269). This heterogenic phenotype difference is common in CDGs. Evidence supporting this gene-disease relationship include two case-studies and experimental data. There are three identified variants (two missense mutations and one deletion) in MAN2B2 between two case studies. The patient with combined immunodeficiency and developmental delays has consiguous parents from Saudi Arabia has homozygous missense variants in MAN2B2 (Verheijen et al., PMID: 31775018). At 5 years of age, this patient was reported to have combined immunodeficiency with absolute lymphopenia and thrombocytopenia. The patient had low T and B cell counts and notably increased proportion of terminally differentiated CD8+ cells, and the patient had elevated percentages of circulating plasmablasts. The other patient from China reported only developmental delays and was identified to have heterozygous compound variants (one missense, one inframe deletion) in MAN2B2 (Tian et al. PMID:35637269). While there are only two known cases, this gene-disease relationship is also supported by experimental evidence like functional studies and rescues in patient cells (Verheijen et al., PMID: 31775018) and (Tian et al. PMID:35637269). In a healthy subject, MAN2B2 is a core-specific α-1,6-mannosidase involved in lysosomal glycoprotein degradation. MAN2B2 cleaves the α-1,6-mannose residue and Man2GlcNAc1 to generate free monosaccharides. The specific impact of the MAN2B2 variants are not fully understood. However, functional experiments included in both case-level publications support the hypothesis that patients with MAN2B2 variants have impaired glycosylation and N-glycan synthesis as there is an abundance of glycans in their cells (Verheijen et al., PMID: 31775018) and (Tian et al. PMID:35637269). Verheijen et al. also saw a rescue of glycosylation with the wild-type MAN2B2 in patient cells (Verheijen et al., PMID: 31775018). While these experimental studies suggests MAN2B2 variants are related to impaired glycosylation in patients with this type of CDG, there is a lack of understanding on the mechanisms behind the connection. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. By diagnosing more patients with this specific type of CDG through genetic testing more evidence on this relationship may be gathered (Tian et al. PMID:35637269). This classification was approved by the ClinGen SCID-CID GCEP on the meeting date [January, 18, 2024] (SOP Version [10]).