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The association between MOGS and congenital disorder of glycosylation is supported by multiple independent case reports and multi‐patient studies. Several reports have described patients with biallelic MOGS mutations, including familial segregation in affected siblings, which provides strong clinical evidence. In one study, two siblings with prolonged survival and variable mutation patterns illustrated that even mosaicism may contribute to the clinical spectrum (PMID:26805780). The clinical phenotype includes dysmorphic facial features, global developmental delay, decreased liver function, visual impairment, and hypoplasia of the corpus callosum. Together, these clinical findings form a consistent pattern that aids in diagnostic decision‑making.
Genetic evidence further underpins the association with an autosomal recessive inheritance mode. Notably, a compound heterozygous variant, c.370C>T (p.Gln124Ter), has been identified in unrelated probands (PMID:31925597). Additional segregation data from affected families support the contribution of pathogenic MOGS variants to the disorder. Although the total number of probands is limited, the recurrence of similar variant classes and consistent disruption of gene function in multiple patients justifies a moderate level of genetic evidence.
Experimental studies have expanded our understanding of the pathogenic mechanism by demonstrating that loss of MOGS function disrupts proper glycoprotein processing. In vitro assays and cell‑based studies have shown markedly reduced enzyme activity and glycosylation defects that are consistent with the clinical phenotype (PMID:15383536; PMID:17062999). Functional analyses in cellular models, including rescue experiments where wild‑type MOGS restores normal glycosylation, support a haploinsufficiency model for disease pathogenesis. These functional data bridge the gap between molecular defects and clinical manifestations.
Although the rarity of reported cases may be viewed as a limitation, the convergent clinical, genetic, and functional evidence paints a coherent picture. Some studies noted the presence of multiple MOGS genotypes, including detectable wild‑type alleles, which could reflect mosaicism or mitotic recombination that modulates phenotypic severity. There is no evidence of contradictory findings, and all experimental results remain in strong concordance with the diagnosed condition. This integrated evidence supports the role of MOGS mutations as causative for congenital disorder of glycosylation.
The evidence integration suggests that while the number of reviewed probands is modest, the combination of familial segregation, recurrent variant detection such as c.370C>T (p.Gln124Ter), and robust functional data provides a clinically meaningful assessment. The use of advanced molecular diagnostic methods, including whole exome sequencing and quantitative glycomics, has further enhanced our ability to detect these rare mutations. This ensures that clinicians can confidently apply these findings in the diagnostic laboratory and in patient management decisions.
Key take‑home: The cumulative genetic and functional data substantiate a moderate gene‑disease association for MOGS with congenital disorder of glycosylation, thereby emphasizing its significance in clinical diagnostics and personalized treatment strategies.
Gene–Disease AssociationModerateMultiple independent case reports involving at least 6 probands (PMID:31925597) and familial segregation in siblings (PMID:26805780) support the association. Genetic EvidenceModerateIdentification of compound heterozygous variants, including c.370C>T (p.Gln124Ter), in unrelated patients establishes the genetic link (PMID:31925597). Functional EvidenceModerateFunctional assays demonstrate reduced MOGS activity and corresponding glycosylation defects consistent with patient phenotypes (PMID:15383536; PMID:17062999). |