@article {Haijesjmedgenet-2017-104586, author = {Hanneke A. Haijes and Jaak Jaeken and Fran{\c c}ois Foulquier and Peter M. van Hasselt}, title = {Hypothesis: lobe A (COG1{\textendash}4)-CDG causes a more severe phenotype than lobe B (COG5{\textendash}8)-CDG}, elocation-id = {jmedgenet-2017-104586}, year = {2017}, doi = {10.1136/jmedgenet-2017-104586}, publisher = {BMJ Publishing Group Ltd}, abstract = {The conserved oligomeric Golgi (COG) complex consists of eight subunits organized in two lobes: lobe A (COG1{\textendash}4) and lobe B (COG5{\textendash}8). The different functional roles of COG lobe A and lobe B might result in distinct clinical phenotypes in patients with COG-CDG (congenital disorders of glycosylation). This hypothesis is supported by three observations. First, knock-down of COG lobe A components affects Golgi morphology more severely than knock-down of COG lobe B components. Second, nearly all of the 27 patients with lobe B COG-CDG had bi-allelic truncating mutations, as compared with only one of the six patients with lobe A COG-CDG. This represents a frequency gap which suggests that bi-allelic truncating mutations in COG lobe A genes might be non-viable. Third, in support, large-scale exome data of healthy adults (Exome Aggregation Consortium (ExAC)) underline that COG lobe A genes are less tolerant to genetic variation than COG lobe B genes. Thus, comparable molecular defects are more detrimental in lobe A COG-CDG than in lobe B COG-CDG. In a larger perspective, clinical phenotypic severity corresponded nicely with tolerance to genetic variation. Therefore, genomic epidemiology can potentially be used as a photographic negative for mutational severity.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/early/2017/08/27/jmedgenet-2017-104586}, eprint = {https://jmg.bmj.com/content/early/2017/08/27/jmedgenet-2017-104586.full.pdf}, journal = {Journal of Medical Genetics} }