An ALG12-CDG patient with a novel homozygous intronic mutation associated with low ALG12 mRNA

Type I Congenital Disorders of Glycosylation (CDG-I) are inherited diseases presenting deficits in protein N-glycosylation involving either the biosynthesis of the lipid-linked oligosaccharide Glc₃Man₉GlcNAc₂-PP-dolichol or transfer of its oligosaccharide to protein.

We describe a patient harbouring hypoglycosylated transferrin, a characteristic of CDG-I. NGS revealed a homozygous RFT1 (c.16G > T p.Val6Leu) variant of unknown significance that is predicted to be benign. Metabolic radiolabelling of the patient's fibroblasts did not reveal the accumulation of truncated Man₅GlcNAc₂-PP-dolichol expected of RFT1-CDG but rather an accumulation of Man₇GlcNAc₂-PP-dolichol, characteristic of ALG12-CDG. Revaluation of the NGS data revealed a homozygous (22_50311909A_G, c.-79 + 2 T > C) variant that modifies the second nucleotide of the first intron of the ALG12 gene upstream of the first coding exon (exon 2). Sequencing of ALG12 cDNA revealed a 4-base insertion between exon 1 and exon 2 suggesting a shift in mRNA splicing in this intron to a putative new GU donor site. The patient's fibroblasts display 3% of control ALG12 mRNA levels.

This is the first description of a pathogenic intronic ALG12 variant upstream of the first coding exon. The modification of the splicing process between intron 1 and exon 2, the very low transcript level and the absence of other mutations in the patient's ALG12 gene lead us to conclude that this ALG12 variant is a predicted Loss of Function (pLOF) variant.