The following is a summary of “TREX1 p.A129fs and p.Y305C variants in a large multi-ethnic cohort of CADASIL-like unrelated patients,” published in the March 2023 issue of the Neurobiology of Aging by Foddis et al.

Rare monogenic early-onset cerebral small vessel disease most commonly takes the form of either cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S). There is a high degree of clinical, neuroradiological, and neuropathological overlap between these disorders.

CADASIL and RVCL-S share overlapping symptoms, although it is still unclear whether this is due to a common genetic risk or to causative variables such as TREX1 coding variants. A sizeable multi-ethnic cohort of 180 early-onset independent familial and sporadic Caucasian patients with symptoms similar to CADASIL was screened for TREX1 protein-coding variability using exome sequencing. These patients were in the United States, Portugal, Finland, Serbia, and Turkey. 

Researchers did this to test a theory that seemed intriguing. Researchers report two sporadic and almost undoubtedly pathogenic TREX1 mutations: a loss of function mutation (p.Ala129fs) clustering in the catalytic domain in a 46-year-old patient from the United States and a missense mutation (p.Tyr305Cys) in the well conserved C-terminal region, in a 57-year-old patient with a positive family history from Serbia. Patients carrying both mutations were identified. Together, the results of the researcher’s study and those of more recent studies expand the list of diseases associated with TREX1 mutations.

Source: sciencedirect.com/science/article/abs/pii/S0197458022002433