Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
ALG12 has been robustly associated with congenital disorder of glycosylation (CDG), a multisystem syndrome resulting from impaired N-linked glycan biosynthesis. Multiple independent studies have identified biallelic pathogenic variants in ALG12 in patients exhibiting features such as psychomotor retardation, hypotonia, growth delay, and dysmorphic features (PMID:12217961).
Genetic evidence supports an autosomal recessive inheritance mode, with patients frequently demonstrating compound heterozygosity or homozygosity for a spectrum of variant types including missense, frameshift, and splicing mutations. For example, one notable variant is c.436C>G (p.Arg146Gly), which has been reported in a case with impaired ALG12 activity (PMID:12217961). Segregation analysis in several families further reinforces that other affected relatives inherit ALG12 variants consistent with an autosomal recessive pattern.
In-depth case reports and multi‐patient studies have detailed a wide phenotypic spectrum with key symptoms that include anorexia, hypotonia, and growth delay, with the clinical picture further extended in some reports to include ocular abnormalities and genitourinary defects (PMID:31529350; PMID:38717015). This phenotypic heterogeneity underscores the importance of detailed clinical and biochemical evaluation when ALG12 variants are identified.
Functional studies have provided compelling evidence of pathogenicity. In vitro assays using patient fibroblasts and yeast complementation models demonstrated that mutations in ALG12 lead to loss of alpha1,6-mannosyltransferase activity, resulting in the accumulation of intermediate glycan substrates. These experimental observations correlate well with the clinical phenotype and underpin the proposed mechanism of pathogenicity as a loss-of-function defect (PMID:12217961).
While some variability exists in the severity and range of manifestations among patients, no study has provided data that would fundamentally dispute the pathogenic role of ALG12 variants in CDG. Minor differences in clinical expressivity may reflect genetic or environmental modifiers rather than a conflicting etiology.
In summary, the integration of genetic and functional data establishes a strong association between ALG12 and congenital disorder of glycosylation. This robust evidence base supports its utility in clinical diagnostic decision-making, offers actionable insights for commercial testing, and provides a sound framework for future publication.
Gene–Disease AssociationStrongMultiple unrelated probands with biallelic ALG12 variants, consistent autosomal recessive segregation, and robust functional studies support the association (PMID:12217961, PMID:31529350). Genetic EvidenceStrongSeveral case reports and multi-patient studies have identified a diverse spectrum of pathogenic variants—including missense and frameshift mutations such as c.436C>G (p.Arg146Gly) in multiple independent families, confirming the gene’s contribution to CDG (PMID:38717015). Functional EvidenceStrongFunctional assays in yeast models and patient fibroblasts demonstrated loss of ALG12 mannosyltransferase activity, correlating with the clinical phenotype and underpinning a loss-of-function mechanism (PMID:12217961). |