ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes

Abstract

Pathogenic variants in ALG13 (ALG13 UDP-N-acetylglucosaminyltransferase subunit) cause an X-linked congenital disorder of glycosylation (ALG13-CDG) where individuals have variable clinical phenotypes that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation. Using a highly sensitive, semi-quantitative flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry (ESI-QTOF/MS) N-glycan assay, we report subtle abnormalities in N-glycans that normally account for <0.3% of the total plasma glycans that may increase up to 0.5% in females with the p.(Asn107Ser) variant. Among our 11 unrelated ALG13-CDG individuals, one male had abnormal serum transferrin glycosylation. We describe seven previously unreported subjects including three novel variants in ALG13 and report a milder neurodevelopmental course. We also summarize the molecular, biochemical, and clinical data for the 53 previously reported ALG13-CDG individuals. We provide evidence that ALG13 pathogenic variants may mildly alter N-linked protein glycosylation in both female and male subjects, but the underlying mechanism remains unclear.

Keywords: N-glycans; carbohydrate deficient transferrin; congenital disorders of glycosylation; epilepsy; exome sequencing; mass spectrometry.

FIGURE 1

The representative glycosylation changes identified in the plasma from ALG13-CDG individuals. A, Comparison between the abundance (% total N-glycan) of minor N-glycan species including N-linked GlcNAc₂ (Man0), GlcNAc₂Gal₁ or Man1, GlcNAc₂Man₂ (Man2), and GlcNAc₂Gal₁NeuAc₁(Tetra) in 9 ALG13-CDG patients (in red) and normal controls (in black). Data sets are shown as box and whisker plots with x showing the medium and outliers shown as dots. *** shows significance with P < .0001; ** shows significance with P < .001. B, The isotope envelopes of different plasma transferrin glycoforms from a representative control and a male ALG13-CDG patient. The relative abundance of isotope envelopes of transferrin glycoforms are shown. Marked increases of mono-glycosylated transferrin glycoform at 26.5% and a-glycosylated transferrin at 13% of normal di-glycosylated transferrin glycoform were detected. Mild increases of mono-glycosylated transferrin with one Man₁GlcNAc₂ or Man₂GlcNAc₂ or Man₃GlcNAc₂ are also shown with blue arrows. Trisialo-transferrin is shown by a black arrow with essentially normal abundance