Presentation Information
[PE4-4]Redefine Genetic Spectrum of Hereditary Sensory and Autonomic Neuropathy
○Junhui Yuan, Yujiro Higuchi, Masahiro Ando, Eiji Matsuura, Akiko Yoshimura, Tomonori Nakamura, Yusuke Sakiyama, Hiroshi Takashima (Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan)
Background Non-coding repeat expansions within RFC1 and NOTCH2NLC genes have been lately linked to multisystem neurodegenerative diseases, which also shed light on yet undiagnosed patients with inherited peripheral neuropathies. Aim of this study is to identify genetic basis of patients with hereditary sensory and autonomic neuropathy (HSAN). Methods We collected 79 DNA samples clinically diagnosed with HSAN in Japan. Mutation screening was performed using gene panel sequencing and whole-exome sequencing. Long-range flanking PCR and repeat-primed PCR were applied to analyze repeat expansions in RFC1 and NOTCH2NLC. Results Pathogenic/likely pathogenic variants were identified from genes of WNK1/HSN2 (6 cases), SCN9A (3 cases), NTRK1 (3 cases), and DNMT1 (2 cases). Bi-allelic RFC1 repeat expansions, consisting of [(AAGGG)exp/(AAGGG)exp] (8 cases), [(ACAGG)exp/(ACAGG)exp] (8 cases), and [(AAGGG)exp/(ACAGG)exp] (4 cases), were detected from 20 adult-onset HSAN patients. GGC repeat expansion in NOTCH2NLC was found in 1 case. Haplotype analysis of patients harboring disease-associated repeat expansions in RFC1 revealed distinguishable haplotypes among subgroups with different repeat genotypes. Conclusion This study substantially redefines genetic spectrum of HSAN, where multi-type RFC1 repeat expansions are account for 25.3% of all patients, highlighting the necessity of genetic screening, particularly for the adult-onset patients. Haplotype variations around RFC1 broadens our understanding in terms of the ancestral origin of these disease-associated repeat expansions.