A coding CAG repeat expansion in EP400 causes Spinocerebellar Ataxia

EP400

Heterozygous expansion of a coding (polyglutamine) CAG repeat in EP400, 37 to 55 repeats, with loss of the CAA interruption present on normal alleles

This preprint screens genome sequencing data from 266 individuals of European and Asian ancestry, mostly patients with dystonia or ataxia plus unaffected participants, for genome-wide repeat expansions using the STRling caller. A polyglutamine-encoding CAG expansion in EP400 was first found in two patients with ataxia, then screened by fragment analysis in 436 further patients with ataxia and 427 matched controls: in total, 18 patients from 14 families carried a heterozygous expansion, all from Serbia. Patient alleles carried 37 to 55 repeats, versus at most 32 in controls, and targeted long-read sequencing showed that the CAA interruption in the 5' CAG tract of non-expanded alleles is lost in expanded alleles. The phenotype is pure spinocerebellar ataxia with onset mainly in the 40s and 50s, and repeat number correlates inversely with age at onset.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

EP400 is not a new gene — point variants are already associated with a neurodevelopmental disorder with epilepsy (PMID 39708813) — but it is a new expansion locus for ataxia, with an unrelated phenotype. The expansion was detected in short-read genomes with a dedicated caller: the point is to add this locus to systematic repeat-expansion screening when analysing an ataxia genome. Limitations: all carriers are Serbian, family segregation is not detailed, the founder-effect test result is not given in the abstract, and this is a preprint.

Analysis by Dr Thibaut Benquey