Heterozygous and Homozygous Repeat Expansions are Common in Idiopathic Peripheral Neuropathy.

OBJECTIVE

Biallelic intronic AAGGG repeat expansions in cause Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome and may also contribute to isolated sensory neuropathy. The clinical significance of both heterozygous and biallelic expansions in more diverse patient populations remains unclear-partly due to the absence of accurate, user-friendly computational tools specifically tailored for tandem repeat analysis.

METHODS

To discern the relationship between expansions and idiopathic peripheral neuropathy (iPN), we performed whole-genome sequencing (WGS) followed by PCR-based confirmation in a large, well-characterized U.S. cohort consisting of 788 iPN patients (369 pure small fiber neuropathy (SFN), 266 sensorimotor, 144 pure sensory, and 9 pure motor). We developed an integrative pipeline combining ExpansionHunter Denovo and Expansion Hunter coupled with unsupervised clustering to reliably detect and genotype expansions from short-read WGS data, achieving 98.2% concordance with repeat-primed PCR based validation.

RESULTS

Biallelic expansions were absent in 879 controls but present in 2.8% of iPN patients (Fisher's exact = 5.9×10 ), including 6.2% of pure sensory, 2.2% of SFN, and 1.5% of sensorimotor neuropathy, indicating that motor nerve involvement should not exclude patients from repeat screening. We also observed a markedly increased frequency of monoallelic expansions in iPN compared to controls (13.2% versus 2.5%; Fisher's exact = 3.4×10 ), without evidence of secondary mutations or expansions on the other allele.

INTERPRETATION

Our approach provides a robust, cost-effective method for detecting expansions from WGS data. Our findings indicate that both heterozygous and homozygous AAGGG repeat expansions in can contribute to development of iPN.