ALG8 – ALG8-congenital disorder of glycosylation

The association between ALG8 and ALG8-congenital disorder of glycosylation is robustly supported by multiple independent studies describing autosomal recessive inheritance in 16 unrelated probands (3 homozygous, 13 compound heterozygous) with congruent clinical and biochemical phenotypes PMID:26066342; PMID:22306853. Based on ClinGen criteria, this meets the requirements for a Strong clinical validity classification.

ALG8-CDG follows autosomal recessive inheritance. Pathogenic variants include missense, truncating, and frameshift changes affecting conserved regions of the α-1,3-glucosyltransferase enzyme. A representative allele, c.121C>T (p.Arg41Ter), has been identified in multiple patients and segregates with disease in homozygous or compound heterozygous states PMID:26066342.

Biochemical assessment consistently reveals a type I transferrin glycosylation pattern, confirming loss-of-function of ALG8 in the endoplasmic reticulum glycan assembly pathway PMID:22306853. These findings support a Moderate tier of functional evidence under ClinGen guidelines.

Clinically, ALG8-CDG presents prenatally or neonatally with multisystem involvement: neurological features including hypotonia (HP:0001252), seizures (HP:0001250), and ataxia (HP:0001251); craniofacial dysmorphism such as low-set ears (HP:0000369), hypertelorism (HP:0000316), and macroglossia (HP:0000158); ocular findings including cataracts (HP:0000518) and visual impairment (HP:0000505); as well as protein-losing enteropathy (HP:0002243), edema (HP:0000969), and coagulopathy.

No conflicting evidence has been reported to date. Together, the genetic and functional data confirm that loss-of-function variants in ALG8 cause a severe autosomal recessive congenital disorder of glycosylation. Key take-home: ALG8 sequencing is recommended in patients with a type I CDG transferrin profile to establish a definitive diagnosis.

References

• European journal of medical genetics • 2012 • Severe ALG8-CDG (CDG-Ih) associated with homozygosity for two novel missense mutations detected by exome sequencing of candidate genes. PMID:22306853
• Orphanet journal of rare diseases • 2015 • ALG8-CDG: novel patients and review of the literature. PMID:26066342

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