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Background <p>Type I Congenital Disorders of Glycosylation (CDG-I) are inherited diseases presenting deficits in protein <i>N</i>-glycosylation involving either the biosynthesis of the lipid-linked oligosaccharide Glc<sub>3</sub>Man<sub>9</sub>Glc<i>N</i>Ac<sub>2</sub>-PP-dolichol or transfer of its oligosaccharide to protein.</p> Results <p>We describe a patient harbouring hypoglycosylated transferrin, a characteristic of CDG-I. NGS revealed a homozygous <i>RFT1</i> (c.16G &gt; 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 Man<sub>5</sub>Glc<i>N</i>Ac<sub>2</sub>-PP-dolichol expected of RFT1-CDG but rather an accumulation of Man<sub>7</sub>Glc<i>N</i>Ac<sub>2</sub>-PP-dolichol, characteristic of ALG12-CDG. Revaluation of the NGS data revealed a homozygous (22_50311909A_G, c.-79 + 2&#xa0;T &gt; C) variant that modifies the second nucleotide of the first intron of the <i>ALG12</i> gene upstream of the first coding exon (exon 2). Sequencing of <i>ALG12</i> 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 <i>ALG12</i> mRNA levels.</p> Conclusion <p>This is the first description of a pathogenic intronic <i>ALG12</i> 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 <i>ALG12</i> variant is a predicted Loss of Function (pLOF) variant.</p>

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

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  • 发表日期：

    2025年2月21日

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  • Sandrine Vuillaumier-Barrot,
  • Thierry Dupré,
  • Tiffany Andriantsihoarana,
  • Vincent Desportes,
  • David Cheillan,
  • Stuart E. H. Moore,
  • Isabelle Chantret

摘要

Background

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.

Results

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.

Conclusion

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.