Expanding the phenotype, genotype and biochemical knowledge of ALG3‐CDG

Abstract

Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multi‐system diseases. Individuals with ALG3‐CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies and feeding difficulties. We present ten unreported individuals diagnosed with ALG3‐CDG based on molecular and biochemical testing with eleven novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3‐CDG, we expand the symptomatology of ALG3‐CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency and renal anomalies. N‐glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man₅GlcNAc₂ consistent with their truncated lipid‐linked precursor oligosaccharides. This spectrum of N‐glycan changes is unique to ALG3‐CDG. These expanded features of ALG3‐CDG facilitates diagnosis and suggests that optimal management should include baseline endocrine, renal, cardiac and immunological evaluation at the time of diagnosis and with ongoing monitoring.