Homozygous truncating variant inMAN2A2causes a novel congenital disorder of glycosylation with neurological involvement

Abstract

BackgroundEnzymes of the Golgi implicated in N-glycan processing are critical for brain development, and defects in many are defined as congenital disorders of glycosylation (CDG). Involvement of the Golgi mannosidase, MAN2A2 has not been identified previously as causing glycosylation defects.MethodsExome sequencing of affected individuals was performed with Sanger sequencing of theMAN2A2transcript to confirm the variant. N-glycans were analysed in patient-derived lymphoblasts to determine the functional effects of the variant. A cell-based complementation assay was designed to assess the pathogenicity of identified variants using MAN2A1/MAN2A2 double knock out HEK293 cell lines.ResultsWe identified a multiplex consanguineous family with a homozygous truncating variant p.Val1101Ter in MAN2A2. Lymphoblasts from two affected brothers carrying the same truncating variant showed decreases in complex N-glycans and accumulation of hybrid N-glycans. On testing of this variant in the developed complementation assay, we see the complete lack of complex N-glycans.ConclusionOur findings show that pathogenic variants in MAN2A2 cause a novel autosomal recessive CDG with neurological involvement and facial dysmorphism. Here, we also present the development of a cell-based complementation assay to assess the pathogenicity of MAN2A2 variants, which can also be extended to MAN2A1 variants for future diagnosis.