Severe ALG8-CDG (CDG-Ih) associated with homozygosity for two novel missense mutations detected by exome sequencing of candidate genes
Sorte, Hanne × Mørkrid, Lars Rødningen, Olaug Kulseth, Mari Ann Stray-Pedersen, Asbjørg Matthijs, Gert Race, Valerie Houge, Gunnar Fiskerstrand, Torunn Bjurulf, Bjørn Lyle, Robert Prescott, Trine #
European Journal of Medical Genetics vol:55 issue:3 pages:196-202
Posttranslationally glycosylated proteins are important in many biological processes in humans and congenital defects of glycosylation (CDGs) are associated with a broad range of phenotypes. Type I CDGs are a group of rare autosomal recessive conditions. To date 17 subtypes have been enzymatically and molecularly characterized. Impaired function of the enzyme dolichyl pyrophosphate Glc(1)Man(9)GlcNAc(2) alpha-1,3-glucosyltransferase encoded by the ALG8 gene, causes ALG8-CDG (CDG-Ih, OMIM #608104). This enzyme facilitates the transfer of a second glucose molecule to a growing lipid-linked oligosaccharide chain, a process that transpires in the endoplasmic reticulum (ER). We present a female patient of consanguineous parents, with pre- and postnatal growth retardation, dysmorphic features, significant developmental delay, visual impairment and an electrophoretic serum transferrin pattern indicative of a type I CDG. Type I CDG subgroup was determined by exome sequencing facilitated by homozygosity analysis. The patient was homozygous for two variants, nine nucleotides apart, in exon 8 of ALG8; c.799T > C [p.Ser267Pro] and c.808T > C [p.Phe270Leu]. Both missense mutations are predicted to affect a conserved region of an intraluminal ER loop of dolichyl pyrophosphate Glc(1)Man(9)GlcNAc(2) alpha-1,3-glucosyltransferase. To our knowledge, the current report describes the ninth published case of ALG8-CDG, contributing to the further delineation of this rare and variable disorder.