AGG repeat expansion and aggregation of BIN1 in multiple system atrophy.

AGG repeat expansion in the first intron of BIN1, detected by long-read sequencing, associated with aggregation of the BIN1 protein in glial cytoplasmic inclusions.

Multiple system atrophy is a fatal, sporadic alpha-synucleinopathy characterised by glial cytoplasmic inclusions in oligodendrocytes, with no causative gene identified to date. Whole-genome sequencing of a patient with familial multiple system atrophy revealed an AGG repeat expansion in the first intron of BIN1, identified by long-read sequencing. Screening for this expansion covered 224 clinically diagnosed patients, 67 pathologically confirmed patients, 574 blood controls and 65 brain controls: expansions exceeding 80 repeats were more frequent in the pathological group than in brain controls (13.4% vs 0%, P = 0.003), with no significant difference in the clinical group compared with blood controls (4.5% vs 2.4%; odds ratio 1.87; 95% CI 0.8-4.5; P = 0.16). Neuropathology showed BIN1-positive glial cytoplasmic inclusions more frequently in expansion carriers, and immunoblotting showed increased insoluble BIN1 in affected brains irrespective of repeat status.

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The divergence between the two cohorts is the central point: the signal appears only in the pathologically confirmed group, which argues as much for heterogeneity of the clinical diagnosis of multiple system atrophy as for a true effect — and rules out any diagnostic use of this expansion for now. The increase in insoluble BIN1 irrespective of repeat status further suggests that aggregation lies downstream of a more general mechanism, of which the expansion would be only one entry point. The bioinformatic interest lies elsewhere: this intronic expansion was beyond the reach of short-read sequencing, a reminder that an already sequenced genome deserves a long-read re-read when no cause is found.

Analysis by Dr Thibaut Benquey