A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N‐glycans in patient's serum

• Published in: American journal of medical genetics. Part A Vol. 185; no. 11; pp. 3494 - 3501
• Main Authors: Ziburová, Jana, Nemčovič, Marek, Šesták, Sergej, Bellová, Jana, Pakanová, Zuzana, Siváková, Barbara, Šalingová, Anna, Šebová, Claudia, Ostrožlíková, Mária, Lekka, Dimitra‐Evanthia, Brucknerová, Jana, Brucknerová, Ingrid, Skokňová, Martina, Mc Cullough, Alexandra, Hrčková, Gabriela, Hlavatá, Anna, Bzdúch, Vladimír, Mucha, Ján, Baráth, Peter
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.11.2021; Wiley Subscription Services, Inc
• Subjects: ALG12‐CDG; Amino acid substitution; CDG Ig; Chromosome 22; Congenital Disorders of Glycosylation - epidemiology; Congenital Disorders of Glycosylation - genetics; Congenital Disorders of Glycosylation - pathology; Enzymatic activity; Female; Genetic analysis; Genetic Predisposition to Disease; Genetic Testing; Glycosylation; Homozygote; Humans; Infant; Infant, Newborn; Isoelectric focusing; Male; Mannosyltransferases - genetics; Mass spectroscopy; Metabolic disorders; Mutation; Mutation, Missense - genetics; N‐glycans; Original; Patients; Phenotype; Polysaccharides; Polysaccharides - genetics; Polysaccharides - metabolism; Slovakia - epidemiology; Transferrin; Transferrin - genetics; Slovakia; ALG12-CDG; CDG Ig; N-glycans
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62474

Congenital disorder of glycosylation type Ig (ALG12‐CDG) is a rare inherited metabolic disease caused by a defect in alpha‐mannosyltransferase 8, encoded by the ALG12 gene (22q13.33). To date, only 15 patients have been diagnosed with ALG12‐CDG globally. Due to a newborn Slovak patient's clinical and biochemical abnormalities, the isoelectric focusing of transferrin was performed with observed significant hypoglycosylation typical of CDG I. Furthermore, analysis of neutral serum N‐glycans by mass spectrometry revealed the accumulation of GlcNAc2Man5–7 and decreased levels of GlcNAc2Man8–9, which indicated impaired ALG12 enzymatic activity. Genetic analysis of the coding regions of the ALG12 gene of the patient revealed a novel homozygous substitution mutation c.1439T>C p.(Leu480Pro) within Exon 10. Furthermore, both of the patient's parents and his twin sister were asymptomatic heterozygous carriers of the variant. This comprehensive genomic and glycomic approach led to the confirmation of the ALG12 pathogenic variant responsible for the clinical manifestation of the disorder in the patient described.