B4GALT1-congenital disorders of glycosylation: Expansion of the phenotypic and molecular spectrum and review of the literature

Abstract

A congenital disorder of glycosylation due to biallelic mutations in B4GALT1 has been previously reported in only three patients with two different mutations. Through homozygosity mapping followed by segregation analysis in an extended pedigree, we identified three additional patients homozygous for a novel mutation in B4GALT1, expanding the phenotypic spectrum of the disease. The patients showed a uniform clinical presentation with intellectual disability, marked pancytopenia requiring chronic management, and novel features including pulmonary hypertension and nephrotic syndrome. Notably, affected individuals exhibited a moderate elevation of Man3GlcNAc4Fuc1 on serum N-glycan analysis, yet two of the patients had a normal pattern of transferrin glycosylation in repeated analysis. The novel mutation is the third disease-causing variant described in B4GALT1, and the first one within its transmembrane domain.

Keywords: cholestasis; congenital disorders of glycosylation; nephrotic syndrome; persistent pulmonary hypertension of the newborn; seizures; thrombocytopenia.

Figure 1.. Disease phenotype:

(A) Pedigree of the consanguineous Bedouin kindred studied. (B) Patient A1’s brain MRI, age 6 years. No pathologic findings were seen except for bilateral choroid plexus xantogranulomas. (C) Homozygosity-Mapper plot. (D) Patient A2’s brain MRI, age 17 months; no pathologic findings except signs of past bleeding. (E) Multiple sequence alignment of selected B4GALT1 orthologues. The p.(R185W) missense mutation affects a highly conserved positive residue and dramatically changes its polarity, within the predicted transmembrane region of the protein. (F) Sanger sequencing. (G) Domain analysis of B4GALT1 with known and novel variants marked.

Figure 2.. Glycosylation studies:

Serum total N-glycan analysis for patients A-1 (A), A-2 (B), their mother (C) and father (D). Moderate elevation of Man3GlcNAc4Fuc1 (m/z 1836) evident in both affected individuals.