MAN1B1 – Rafiq syndrome

MAN1B1 (HGNC:6823) is implicated in Rafiq syndrome (MONDO:0013624), an autosomal recessive congenital disorder of glycosylation type II. The syndrome manifests with global developmental delay, intellectual disability, hypotonia, facial dysmorphism, truncal obesity, and variable additional features. Clinical diagnosis integrates abnormal transferrin glycosylation profiles with genomic sequencing of MAN1B1 variants.

Genetic evidence includes at least 15 probands from ≥13 unrelated families demonstrating a consistent autosomal recessive inheritance. Compound heterozygous variants, such as splice-donor c.1065+1G>C and missense c.1000C>T (p.Arg334Cys), were reported in a Russian patient ([PMID:36142510]). A homozygous missense variant c.1976T>G (p.Phe659Cys) was identified in a Palestinian child ([PMID:39840888]), and recurrent c.1000C>T (p.Arg334Cys) was observed in unrelated cases ([PMID:39896699]). Segregation analysis in consanguineous families and sibships confirmed trans configuration with at least 2 additional affected relatives.

The variant spectrum comprises >20 pathogenic alleles including missense (e.g., p.Arg334Cys, p.Phe659Cys), splice-site (c.1065+1G>C), frameshift, and nonsense variants in both homozygous and compound heterozygous states. Recurrent missense alleles suggest possible founder effects in diverse populations.

Functional studies using high-resolution mass spectrometry revealed a characteristic hybrid-type N-glycan signature in an index patient and 11 additional cases ([PMID:24566669]). Enzymatic assays in patient-derived cells confirmed deficient α1,2-mannosidase activity, and glycoprofiling of total serum proteins, immunoglobulins, and α1-antitrypsin substantiated systemic glycosylation defects. These findings align with the molecular genetic evidence and clinical phenotype.

Together, these data satisfy a Strong ClinGen gene–disease association, supported by 15 probands, autosomal recessive segregation, and concordant functional data. The genetic evidence is Strong based on diverse variant classes and segregation, and the functional evidence is Moderate based on robust glycosylation assays and enzymatic studies.

Genetic screening for MAN1B1 variants alongside transferrin glycoprofiling is recommended for patients presenting with intellectual disability, developmental delay, hypotonia, obesity, and dysmorphic features. Early diagnosis enables targeted management, genetic counseling, and family planning. Key take-home: Biallelic MAN1B1 mutations cause Rafiq syndrome with a reliable functional biomarker, enabling effective diagnostic workflows.

References

• International journal of molecular sciences • 2022 • Case Report: Compound Heterozygous Variants of the MAN1B1 Gene in a Russian Patient with Rafiq Syndrome. PMID:36142510
• Journal of investigative medicine high impact case reports • 2025 • A Case of Rafiq Syndrome (MAN1B1-CDG) in a Palestinian Child, With Brief Literature Review of 44 Cases. PMID:39840888
• Iranian journal of child neurology • 2025 • Rafiq Syndrome: Old Variant in MAN1B1 Gene and Some New Phenotypic Features. PMID:39896699
• Brain : a journal of neurology • 2014 • Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency. PMID:24566669
• Molecular syndromology • 2015 • MAN1B1 Mutation Leads to a Recognizable Phenotype: A Case Report and Future Prospects. PMID:26279649
• Cells • 2021 • Siblings with MAN1B1-CDG Showing Novel Biochemical Profiles. PMID:34831340

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