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The association between MAN1B1 and MAN1B1-congenital disorder of glycosylation is supported by extensive genetic and experimental evidence. This multisystem autosomal recessive disorder presents with intellectual disability, global developmental delay, hypotonia, facial dysmorphisms, and truncal obesity. Initially described in 2010, MAN1B1-CDG was genetically confirmed by pathogenic variants in MAN1B1 in subsequent studies. Over 44 unrelated probands across more than ten families have been documented harboring biallelic MAN1B1 variants (PMID:39840888). Segregation in consanguineous pedigrees further corroborates autosomal recessive inheritance. Functional assays demonstrate consistent glycosylation defects and impaired mannosidase activity in patient samples and model systems. Based on ClinGen criteria, the MAN1B1–MAN1B1-CDG association is classified as Strong.
MAN1B1-CDG is inherited in an autosomal recessive pattern, with most patients carrying homozygous or compound heterozygous variants in MAN1B1. Case series have identified a spectrum of loss-of-function and missense mutations, including 12 truncating alleles and 10 missense substitutions, with recurrent and private variants reported. A representative variant is c.1976T>G (p.Phe659Cys) identified homozygously in a Palestinian child (PMID:39840888). In a cohort of ten patients, transcript analysis revealed both frameshift and splice site mutations underlying a type II glycosylation defect (PMID:26401844). Three additional individuals harbored novel missense and truncating variants, expanding the mutational landscape of MAN1B1-CDG (PMID:34162022). Two siblings with p.Asp613ThrfsTer? demonstrated novel biochemical profiles and early-onset epileptic encephalopathy (PMID:34831340). Overall, the reported genetic diversity and consistent phenotype fulfill strong genetic evidence criteria for autosomal recessive disorders.
Segregation analysis in multiple consanguineous pedigrees has confirmed biallelic inheritance of MAN1B1 variants. In the initial single-patient study, segregation of the candidate variant was validated by parental carrier status (PMID:24566669). Subsequent family studies identified affected siblings in two separate pedigrees, yielding a total of two additional affected relatives (PMID:34831340). Although formal LOD scores are not reported, the co-segregation of rare variants with disease supports causality. No heterozygous carriers exhibit clinical features, consistent with recessive inheritance. These observations underpin a clear genotype–phenotype correlation within families. Such segregation data contribute supplemental evidence but do not solely define the association.
MAN1B1 pathogenic variants encompass missense, nonsense, frameshift, and splice site mutations affecting the alpha-mannosidase catalytic domain. Reported missense substitutions frequently cluster in the catalytic site, abrogating enzymatic activity. LoF alleles include frameshift variants such as c.244C>T (p.Gln82Ter) and c.1177_1178dup (p.Ser393fs), both establishing truncating lesions (PMID:34141584, PMID:24566669). Splice site disruptions, exemplified by c.730+1G>A, lead to exon skipping and loss of function (PMID:24566669). Interestingly, c.1789C>T (p.Arg597Trp) appears recurrently across diverse populations (PMID:34258140). These variants display absence or extreme rarity in control databases. The diversity and recurrence of deleterious alleles across cohorts fulfill variant interpretation guidelines for pathogenicity.
Experimental studies elucidate the pathomechanism of MAN1B1 deficiency as a glycosylation processing defect. High-resolution mass spectrometry of plasma transferrin and total glycoproteins reveals a characteristic hybrid N-glycan signature in affected individuals (PMID:24566669). Quantitative analysis of serum IgG glycosylation in ten patients highlighted novel high-mannose and sialyl Lewis x glycans, underscoring Golgi processing abnormalities (PMID:26401844). Enzymatic assays in patient-derived lymphocytes confirm reduced alpha-1,2 mannosidase activity and aberrant glycan processing (PMID:34831340). Unconventional ER-associated degradation pathways involving the Man1b1 cytoplasmic tail further demonstrate mechanistic roles in protein quality control (PMID:32958677). These concordant functional data substantiate MAN1B1 as the molecular driver of the glycosylation phenotype. Rescue experiments are pending but current evidence meets moderate functional criteria.
In summary, biallelic MAN1B1 variants cause a clinically recognizable congenital disorder of glycosylation with consistent neurological and metabolic features. Strong genetic evidence, reinforced by co-segregation and a diverse pathogenic variant spectrum, aligns with concordant functional glycoprofiling and enzymatic assays. The mechanistic understanding of defective Golgi mannosidase activity integrates genotype and phenotype, enabling confident molecular diagnosis. Although additional functional studies, including in vivo models and rescue experiments, could further elucidate pathogenesis, current data suffice for diagnostic decision-making. This gene–disease relationship supports genetic counseling, carrier screening, and potential therapeutic exploration. Take-home: MAN1B1 deficiency should be considered in patients with unexplained intellectual disability and glycosylation abnormalities due to its robust clinical validity.
Gene–Disease AssociationStrong44 probands across >10 families; consistent autosomal recessive segregation; concordant functional data Genetic EvidenceStrong44 probands, 12 truncating and 10 missense variants; autosomal recessive inheritance Functional EvidenceModerateConsistent glycoprofiling and ERAD assays demonstrating impaired MAN1B1 activity |