Congenital disorders of glycosylation comprise a group of genetic defects with a high frequency of
intellectual disability, caused by deficient glycosylation of
proteins and
lipids. The molecular basis of the majority of the
congenital disorders of glycosylation type I subtypes, localized in the cytosol and endoplasmic reticulum, has been solved. However, elucidation of causative genes for defective Golgi glycosylation (
congenital disorders of glycosylation type II) remains challenging because of a lack of sufficiently specific diagnostic serum methods. In a single patient with
intellectual disability, whole-exome sequencing revealed MAN1B1 as
congenital disorder of glycosylation type II candidate gene. A novel mass spectrometry method was applied for high-resolution glycoprofiling of intact plasma
transferrin. A highly characteristic glycosylation signature was observed with hybrid type N-
glycans, in agreement with deficient
mannosidase activity. The speed and robustness of the method allowed subsequent screening in a cohort of 100 patients with
congenital disorder of glycosylation type II, which revealed the characteristic glycosylation profile of MAN1B1-congenital disorder of glycosylation in 11 additional patients. Abnormal hybrid type N-
glycans were also observed in the glycoprofiles of total
serum proteins, of enriched
immunoglobulins and of alpha1-antitrypsin in variable amounts. Sanger sequencing revealed MAN1B1 mutations in all patients, including severe truncating mutations and amino acid substitutions in the
alpha-mannosidase catalytic site. Clinically, this group of patients was characterized by
intellectual disability and delayed motor and speech development. In addition, variable dysmorphic features were noted, with truncal
obesity and
macrocephaly in ∼65% of patients. In summary, MAN1B1 deficiency appeared to be a frequent cause in our cohort of patients with unsolved
congenital disorder of glycosylation type II. Our method for analysis of intact
transferrin provides a rapid test to detect MAN1B1-deficient patients within
congenital disorder of glycosylation type II cohorts and can be used as efficient diagnostic method to identify MAN1B1-deficient patients in
intellectual disability cohorts. In addition, it provides a functional confirmation of MAN1B1 mutations as identified by next-generation sequencing in individuals with
intellectual disability.