A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype

Abstract

Congenital disorders of glycosylation (CDG) are a large group of recessive multisystem disorders caused by impaired protein or lipid glycosylation. The CDG-I subgroup is characterized by protein N-glycosylation defects originating in the endoplasmic reticulum. The genetic defect is known for 17 different CDG-I subtypes. Patients in the few reported DPAGT1-CDG families exhibit severe intellectual disability (ID), epilepsy, microcephaly, severe hypotonia, facial dysmorphism and structural brain anomalies. In this study, we report a non-consanguineous family with two affected adults presenting with a relatively mild phenotype consisting of moderate ID, epilepsy, hypotonia, aggressive behavior and balance problems. Exome sequencing revealed a compound heterozygous missense mutation, c.85A4T (p.I29F) and c.503T4C (p.L168P), in the DPAGT1 gene. The affected amino acids are located in the first and fifth transmembrane domains of the protein. Isoelectric focusing and high-resolution mass spectrometry analyses of serum transferrin revealed glycosylation profiles that are consistent with a CDG-I defect. Our results show that the clinical spectrum of DPAGT1-CDG is much broader than appreciated so far.

High-resolution mass spectrometry glycoprofiling of intact transferrin for diagnosis and subtype identification in the congenital disorders of glycosylation

“…For galactosemia, no truncated glycans could be observed lacking galactose, in correspondence with the literature (Supplemental Data Fig 2, C). 27 For mild to near-normal type 1 profiles, 28 for example in fructosemia (Supplemental Data Fig 2, D), DPAGT1-CDG, 29 or mild PMM2-CDG cases, 30 a loss of intact glycans was observed with high sensitivity Q18 . On fructose-free diet, the transferrin isofocusing profile of a fructosemia patient normalized completely, whereas QTOF MS still showed minimal loss of a single complete glycan (data not shown).…”

Clinical utility gene card for: DPAGT1 defective congenital disorder of glycosylation

“…Twenty-five variants have been reported: twenty-one missense variants, three splicing variants and one duplication vari ant [1][2][3][4][5][6][7][8][9][10][11] (www.lovd.nl/DPAGT1). The standard reference sequence indicating reported variants (ENSG00000172269) and a reference for exon numbering (ENST00000354202) can be found at http://www.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] The frequency and the prevalence of the disease are not known.…”

Making headway with genetic diagnostics of intellectual disabilities

“…In addition, exome sequencing in syndromic forms of AR ID in multiple non-consanguineous families led to the elucidation of the underlying gene defects in AR ID syndromes, such as Dubowitz syndrome (OMIM 223370) and CHIME syndrome (OMIM 280000) (64,65). Reports of the identification of AR ID genes in non-syndromic outbred families by exome sequencing approaches are more rare (66,67). They reported in 54% potentially diseasecausing variants in known and novel candidate ID genes.…”