A splice-altering intronic variant in two multiplex families refines autosomal recessive COG4-related congenital disorder of glycosylation.

Autosomal recessive COG4-related congenital disorder of glycosylation [COG4-CDG(ar)] is caused by biallelic deleterious variants in COG4, which encodes a component of the conserved oligomeric Golgi complex lobe A. COG4-CDG(ar) has been described in six individuals to date, and its clinical manifestations and disease mechanisms remain poorly understood. Exome sequencing identified the homozygous COG4 c.1647+5G>A variant in four affected individuals from two apparently unrelated Italian families. SNP-array genotyping revealed a common ancestral haplotype extending for 3.36 cM around COG4 and supports a founder effect for the identified variant. Whole transcriptome sequencing and reverse transcriptase PCR from peripheral blood detected an aberrant COG4 transcript which features skipping of exon 12 and results in a frameshift, predicted to introduce a premature termination codon. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry profiling of serum N-glycans showed mildly deficient galactosylation and sialylation, consistent with an impaired Golgi-mediated glycosylation. As a novel finding, N-glycosylation study of serum IgG showed analogous N-glycan anomalies. These findings and literature review define COG4-CDG(ar) as a neurometabolic disorder with a progressive course leading to severe global disability, post-natal microcephaly with brain atrophy, seizures, coagulopathy, liver involvement, recurrent infections, and defective N-glycosylation of serum proteins.