Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly

Background Protein disulfide isomerase(PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways. Methods Eight children from four consanguineousfamilies residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephalywith lissencephaly( microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis. Results An identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72repeat expansion toxicity, patients showed no evidence of C9ORF72repeat expansions. Conclusion The TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.