Biallelic missense variants in COG3 cause a congenital disorder of glycosylation with impairment of retrograde vesicular trafficking

Abstract

Biallelic variants in genes for seven out of eight subunits of the conserved oligomeric Golgi complex (COG) are known to cause recessive congenital disorders of glycosylation (CDG) with variable clinical manifestations. COG3 encodes a constituent subunit of the COG complex that has not been associated with disease traits in human. Herein, we report two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families that co‐segregated with COG3‐CDG. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings. Biochemical analysis of serum transferrin from one family showed the loss of a single sialic acid. Western blotting on patient‐derived fibroblasts revealed reduced COG3 and COG4. Further experiments showed delayed retrograde vesicular recycling in patient cells. This report adds to the knowledge of the COG‐CDG network by providing collective evidence for a COG3‐CDG rare disease trait and implicating a likely pathology of the disorder as the perturbation of GA trafficking.This article is protected by copyright. All rights reserved.

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders

“…In contrast, the study of rare genetic variation has only just begun. An explosion of neurodevelopmental disease-gene associations has resulted from family-based studies, next generation sequencing, and online gene matchmaking [ 4 , [111] , [112] , [113] , [114] , [115] , [116] , [117] , [118] , [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] , [127] , [128] ], but genome-wide functional annotation requires greater international integration of human genomic and phenotypic data. National programs like UK Biobank and All of Us represent an important step in this direction [ 129 , 130 ], but a wealth of genomic and phenotypic data remains locked away in data silos: research databases, clinical diagnostic laboratories, and electronic health records.…”