ALG12 and ALG12‑congenital disorder of glycosylation

The association between ALG12 and ALG12‑congenital disorder of glycosylation is supported by multiple independent studies evaluating both genetic and functional evidence. Case reports have demonstrated that patients with severe skeletal dysplasia, including features such as platyspondyly, rhizomelia, joint dislocation, and talipes equinovarus (PMID:25019053), harbor biallelic loss‐of‑function variants in ALG12. These patients typically present with a multisystem phenotype that in some cases overlaps with other congenital disorders of glycosylation.

Genetic evidence highlights an autosomal recessive mode of inheritance, with segregation analyses demonstrating affected siblings in familial studies. Several independent case series and multi‐patient studies report a cumulative total of more than 15 probands diagnosed with ALG12‑CDG (PMID:34467644; PMID:31481313), and multiple families show segregation of pathogenic alleles. In these studies, frameshift and deletion variants (e.g., c.1001del (p.Asn334ThrfsTer15)) have been recurrently identified, further consolidating the genotype–phenotype correlation.

The variant spectrum for ALG12‑CDG is characterized by a variety of deleterious coding changes including frameshift, nonsense, splice site, and indel mutations. In particular, the frameshift variant c.1001del (p.Asn334ThrfsTer15) has been observed in independent reports and serves as a representative molecular event supporting the pathogenic mechanism. These genetic findings are consistent with a loss‐of‑function mechanism that disrupts the enzyme’s role in the proper assembly of dolichol‑linked oligosaccharides.

Functional studies further substantiate the link between ALG12 dysfunction and the clinical presentation of ALG12‑CDG. In patient fibroblasts and in engineered yeast models, reduced enzyme activity and accumulation of aberrant glycosylation intermediates have been documented (PMID:12217961). Complementation assays confirmed that the wild‑type ALG12 allele can restore normal growth phenotypes, while mutant alleles fail to complement, reinforcing the concept that loss‐of‑function underlies disease pathogenesis.

Additionally, the convergence of genetic and functional data across numerous centers, including reports of atypical phenotypes such as hydronephrosis and ocular manifestations, underscores the allelic heterogeneity and phenotypic variability intrinsic to ALG12‑CDG (PMID:38717015; PMID:38876156). This integrated evidence supports a role for ALG12 not only in early glycoprotein biosynthesis, but also in the modulation of a broad clinical spectrum, ranging from typical multisystem involvement to more unusual phenotypes.

In summary, multiple lines of evidence from both case reports and multi‐patient studies converge to support a strong association between biallelic loss‐of‑function variants in ALG12 and ALG12‑CDG. The combination of recurrent frameshift variants, segregation among affected relatives, and corroborative functional assays provides clear and actionable insights for diagnostic decision‑making, commercial applications, and future publication.

Key Take‑home: ALG12‑CDG is a well‐substantiated, autosomal recessive disorder with robust genetic and functional evidence that can guide integrated clinical assessments.

References

• Molecular genetics and metabolism reports • 2014 • Diagnosis of ALG12-CDG by exome sequencing in a case of severe skeletal dysplasia PMID:25019053
• American journal of medical genetics. Part A • 2024 • Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys PMID:38717015
• Journal of AAPOS • 2024 • Duane syndrome in association with congenital disorder of glycosylation type Ig (ALG12-CDG) PMID:38876156
• Glycoconjugate journal • 2019 • ALG12-CDG: novel glycophenotype insights endorse the molecular defect PMID:31529350
• Molecular genetics and metabolism • 2019 • Complex phenotypes in ALG12-congenital disorder of glycosylation: Case series and review of the literature PMID:31481313
• American journal of human genetics • 2016 • Mitotic Intragenic Recombination: A Mechanism of Survival for Several Congenital Disorders of Glycosylation PMID:26805780
• American journal of medical genetics. Part A • 2021 • A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum PMID:34467644
• Brain & development • 2021 • Novel ALG12 variants and hydronephrosis in siblings with impaired N-glycosylation PMID:34092405
• Human molecular genetics • 2002 • ALG12 mannosyltransferase defect in congenital disorder of glycosylation type Ig PMID:12217961
• Molecular genetics & genomic medicine • 2020 • ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant PMID:32530140
• Orphanet journal of rare diseases • 2025 • An ALG12-CDG patient with a novel homozygous intronic mutation associated with low ALG12 mRNA PMID:39984963

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