Edition of 21 October 2021

A new study published in the American Journal of Medical Genetics identified bi-allelic variants EDEM3, causing an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. 11 individuals (from seven independent families) have a protein-truncating variant, and one individual has a compound heterozygous missense variant. Among others pathways, EDEM3 is involved in the recognition and elimination pathways of misfolded proteins. Experiments in various cells and tissues show a loss of the ER quality-control mannosidase, or even suggest an impaired unfolded protein response. The authors present a new biomarker for validating variants of uncertain significance that may be identified by molecular genetic testing.

A new study published in Brain identified a bi-allelic loss-of-function variants in PRDX3, within five unrelated families with mild-to-moderate progressive cerebellar ataxia with concomitant hyper / hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brain stem degeneration. Fibroblasts analyses and experiments (knockdown cells, and in vivo models) reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis, and cerebellar vulnerability.