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.

Congenital disorders of glycosylation type I (CDG-I) are a group of autosomal recessive genetic multisystem disorders that arise from defective glycoprotein biosynthesis. Although ocular abnormalities have been described in patients with CDG-I, few ocular abnormalities have been associated with ALG12-CDG (CDG-Ig), a rare subtype of CDG-I. We report a case of Duane syndrome, a congenital strabismus syndrome, in a 17-year-old young woman with ALG12-CDG.

Congenital disorders of glycosylation (CDG) are a group of rare autosomal recessive genetic disorders caused by pathogenic variants in genes coding for N-glycosylated glycoproteins, which play a role in folding, degrading, and transport of glycoproteins in their pathway. ALG12-CDG specifically is caused by biallelic pathogenic variants in ALG12. Currently reported features of ALG12-CDG include: developmental delay, hypotonia, failure to thrive and/or short stature, brain anomalies, recurrent infections, hypogammaglobulinemia, coagulation abnormalities, and genitourinary abnormalities. In addition, skeletal abnormalities resembling a skeletal dysplasia including shortened long bones and talipes equinovarus have been seen in more severe neonatal presentation of this disorder. We report on a case expanding the phenotype of ALG12-CDG to include bilateral, multicystic kidneys in a neonatal demise identified with homozygous pathogenic variants in the ALG12 gene at c.1001del (p.N334Tfs*15) through clinical trio exome sequencing.

ALG12-CDG is a rare autosomal recessive type I congenital disorder of glycosylation (CDG) due to pathogenic variants in ALG12 which encodes the dolichyl-P-mannose:Man-7-GlcNAc-2-PP-dolichyl-alpha-6-mannosyltransferase. Thirteen patients from unrelated 11 families have been reported, most of them result in broad multisystem manifestations with clinical variability. It is important to validate abnormal glycosylation to establish causal relationship. Here, we report two siblings with novel compound heterozygous variants in ALG12: c.443T>C, p.(Leu148Pro) and c.412_413insCGT, p.(Gln137_Phe138insSer). Both patients showed global developmental delay, microcephaly, hypotonia, failure to thrive, facial dysmorphism, skeletal malformations and coagulation abnormalities, which are common in ALG12-CDG. In addition, one of our patients showed left hydronephrosis, which is a novel clinical feature in ALG12-CDG. Brain MRI showed hypoplasia of cerebrum, brain stem and cerebellar vermis in both patients. N-glycosylation defects of trypsin digested transferrin peptides were revealed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), and electrospray ionization MS verified the lack of N-glycans in transferrin. The present study can add hydronephrosis to phenotypic spectrum of ALG12-CDG. Since the symptoms of ALG12-CDG are quite diverse, the combination of whole-exome sequencing and transferrin glycopeptide analysis with MS, can help diagnosis of ALG12-CDG.

Congenital disorders of glycosylation (CDG) are a group of rare genetic diseases caused by the deficiency of enzymes involved in the biosynthesis or remodeling of the glycan moieties of glycoconjugates. Most of CDG are autosomal recessive; however, few of them show autosomal dominant or X-linked inheritance. ALG12-CDG is an autosomal recessive inherited defect caused by a deficiency in the α-mannosyltransferase, dolichyl-P-mannose: Man7-GlcNAc-2-PP-dolichyl-alpha-6-mannosyltransferase (mannosyltransferase 8), which determines Man7GlcNAc2-PP-dolichol accumulation in tissues including fibroblasts. The clinical features of ALG12-CDG include dysmorphic features, developmental delay, hypotonia, progressive microcephaly, hypogammaglobulinemia, coagulopathies, and failure to thrive. Herein, we describe the case of a Sicilian patient with a milder phenotype bearing an ALG12 homozygous mutation. To date, including this patient, only 16 cases have been described with this form of CDG. Furthermore, our study contributes to understanding the milder ALG12-CDG cases and to further expanding the genotype-phenotype spectrum.