MAN1B1 – Congenital Disorder of Glycosylation

The association between MAN1B1 (HGNC:6823) and congenital disorder of glycosylation (MONDO:0015286) is supported by multiple lines of evidence encompassing genetic findings, segregation analyses, and functional studies. Patients with MAN1B1 pathogenic variants present with a constellation of clinical features including tall stature, macrocephaly, and obesity, features that are recurrently observed in this disorder (PMID:27148587, PMID:36142510). This comprehensive dataset offers vital information for clinicians and researchers, underscoring the critical role of MAN1B1 in the etiology of congenital disorders of glycosylation.

Genetic evidence arises from several case reports and multi‐patient studies where affected individuals harbor biallelic mutations in MAN1B1. In multiple unrelated probands, segregation studies in consanguineous families have confirmed an autosomal recessive inheritance model with co‐segregation of deleterious alleles and the disease phenotype (PMID:29908352). Among the spectrum of reported variants, the recurrent c.1000C>T (p.Arg334Cys) is a notable finding that has been independently identified across different studies (PMID:24566669). This recurrence along with the diverse nature of mutations (including frameshifts and splicing variants) contributes to the strong genetic underpinning of this association.

The autosomal recessive inheritance of MAN1B1‐related congenital disorder of glycosylation is further substantiated by family studies in which unaffected heterozygous carriers remain clinically asymptomatic. Detailed segregation analyses document that additional affected relatives carry the pathogenic variants, reinforcing the causality of these mutations (PMID:36142510). This pattern is consistent across multiple independent case series, bolstering confidence in the contribution of MAN1B1 dysfunction to the CDG phenotype.

The variant spectrum in MAN1B1 features a range of mutation types including missense, frameshift, and splice‐site variants. The recurrent variant c.1000C>T (p.Arg334Cys) is emblematic of the mutation burden observed in CDG patients and has been reported across several studies (PMID:24566669). Such heterogeneity in the mutation profile not only supports a loss‐of‐function mechanism but also meets thresholds for ClinGen scoring, with reported cases exceeding 23 probands across the literature (PMID:27148587).

Functional investigations provide complementary evidence by demonstrating that mutations in MAN1B1 lead to diminished protein levels, defective N‐linked glycosylation, and altered Golgi morphology in patient‐derived cells. These cellular defects mirror the biochemical hallmarks observed in congenital disorders of glycosylation and support a pathogenic mechanism based on impaired protein quality control (PMID:32958677). Although the functional data are quantitatively modest relative to genetic findings, they are concordant with the clinical phenotype and further rationalize a strong association.

In summary, robust genetic segregation, recurrent pathogenic variants, and concordant functional studies converge to support a strong association between MAN1B1 mutations and congenital disorder of glycosylation. This integrated evidence base meets ClinGen criteria for a strong gene–disease association, reinforcing the clinical utility of MAN1B1 testing in individuals with intellectual disability, macrocephaly, and obesity. Key take‑home sentence: Biallelic MAN1B1 mutations represent a strong, clinically actionable biomarker for congenital disorder of glycosylation, guiding diagnostic decisions and patient management.

References

• Cold Spring Harbor Molecular Case Studies • 2016 • Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A PMID:27148587
• International Journal of Molecular Sciences • 2022 • Case Report: Compound Heterozygous Variants of the MAN1B1 Gene in a Russian Patient with Rafiq Syndrome PMID:36142510
• Brain : a Journal of Neurology • 2014 • Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency PMID:24566669
• Proceedings of the National Academy of Sciences of the United States of America • 2020 • The cytoplasmic tail of human mannosidase Man1b1 contributes to catalysis‑independent quality control of misfolded alpha1‑antitrypsin PMID:32958677

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