Abstract
Objectives Peripheral neuropathies (PN) have a prevalence of up to 8% in individuals > 55 years. Consensus suggests clinical evaluation of PN should include screening for acquired causes followed by genetic testing for PMP22, MFN2, GJB1, and MPZ in individuals with a positive family history and symptom onset <50 years. We report outcomes from a retrospective analysis of a sequential cohort of affected individuals referred for genetic testing.
Methods 6,849 adult probands underwent PN multigene panel testing. A molecular diagnosis was defined as either a single pathogenic/likely pathogenic (P/LP) variant in an autosomal dominant or X-linked gene, or two P/LP (homozygous) variants in a recessive gene.
Results Of 6,849 probands, 899 (13.1%) had P/LP variants. PMP22, MFN2, GJB1, MPZ, and TTR accounted for 73% of molecular diagnoses. Of those who tested positive, 84% (231/275) had a positive family history and symptoms appeared at 31.1 years on average. 73/573 (12.7%) could have been missed if genetic testing was not pursued due to: first documented symptoms at age = or > 50; an explicitly stated negative family history; or documentation of a presumed acquired aetiology. 152/573 (26.5%) would be missed if testing was restricted to PMP22, MFN2, GJB1, and MPZ. 225/573 (39.3%) of molecular diagnoses would have been missed if only published indications for genetic testing had been followed.
Conclusion Genetic testing may identify P/LP results in up to 13% of individuals affected with PN. Nearly half of those with P/LP variants would be missed by published genetic testing recommendations.
