Expanding the genetic spectrum of inherited peripheral neuropathies in complex neurogenetic disorders using whole-exome sequencing

Inherited peripheral neuropathies (IPNs) represent a clinically and genetically heterogeneous group of disorders affecting sensory, motor, autonomic functions, and can also present as a part of complex neurogenetic syndromes. Charcot-Marie-Tooth disease (CMT) is the most prevalent type of IPN. Despite advances in genetic testing, the diagnostic process remains challenging due to genetic heterogeneity and overlapping clinical phenotypes. We performed a comprehensive genetic evaluation of 126 patients presenting with symptoms of IPN. Nineteen patients with a typical CMT phenotype were initially screened for PMP22 copy number variations using Multiplex Ligation-dependent Probe Amplification (MLPA). Whole-exome sequencing (WES) was subsequently performed in 107 patients. Of these, 72 (63.7%) were classified as pathogenic or likely pathogenic, including 36 novel variants (50.0%), yielding an overall WES diagnostic rate of 62.6% (67/107). CMT-spectrum disorders identified by MLPA (n = 19 patients) and WES (n = 33 patients) accounted for 41.3% (52/126) of the study cohort. Additional diagnoses included hereditary sensory neuropathy 3.97% (5/126), distal hereditary motor neuropathy 4.76% (6/126), spastic paraplegia 3.97% (5/126), spinocerebellar ataxia 5.56% (7/126), spastic ataxia 8.73% (11/126), mitochondrial disease 7.94% (10/126), and other complex neurogenetic disorders 23.81% (30/126). Our findings highlight the utility of genomic sequencing approaches for resolving clinically heterogeneous neuropathy presentations and demonstrate the value of WES in a highly consanguineous Iranian cohort. These results support the role of WES in advancing precision medicine approaches for inherited neuropathies.