Pseudodominant Inheritance of Biallelic RFC1 Expansions-Revisiting the 3p22-p24 HSN1B Locus

Hereditary sensory neuropathies (HSN) are a group of heterogenous peripheral neuropathies presenting primarily with distal sensory loss. Biallelic expansions in intron 2 of RFC1 (replication factor C subunit 1) can cause autosomal recessive HSN. We aimed to reassess two previously reported families (HSN32 and HSN35) with "autosomal dominant HSN1 with cough and gastroesophageal reflux." The phenotype was designated HSN1B and linked to chromosome 3p22-p24, although no causative variant was identified.

Due to the phenotypic similarities between HSN1B and biallelic RFC1 expansions, targeted long-read sequencing (LRS) of the HSN32 proband was performed. RFC1 expansion analysis was then conducted on available individuals from HSN32 and HSN35 using flanking PCR, repeat-primed PCR (RP-PCR), and targeted LRS.

LRS of the proband (Generation III) from HSN32 revealed a novel complex RFC1 expansion (AGGGC₇₅₀AAGGC₁₅₀) in trans with a known pathogenic AAGGG₈₀₀ expansion. Extended RFC1 analysis showed the proband's affected father (Generation II) reproduced with an unaffected carrier of the novel RFC1 AGGGC₇₅₀AAGGC₁₅₀ expansion to produce the affected proband. Further analysis of the affected father and his four affected siblings (Generation II) identified pathogenic biallelic RFC1 AAGGG_exp expansions inherited from their carrier parents (Generation I). For family HSN35, both affected individuals previously reported in the second HSN1B family had biallelic AAGGG_exp RFC1 expansions.

Affected individuals across consecutive generations in HSN32 resulted in the erroneous mapping of an "autosomal dominant" HSN1B chr3p22-p24 locus. The HSN1B locus should therefore no longer be considered a valid locus for HSN.