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Peer-reviewedCC BYNeurogenetics

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

  • Paria Najarzadeh Torbati1,2
  • Reza Boostani3
  • Mojtaba Safi1
  • Najmeh Ahangari4
  • Mohammad Doosti1
  • Hasan Badpar1
  • Mehran Beiraghi Toosi4
  • Ehsan Ghayoor Karimiani5,6
  • Barbara Vona7,8,9,10,11
11 affiliations
  1. 1Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
  2. 2Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
  3. 3Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
  4. 4Rare Pediatric Neurological Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
  5. 5Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran. [email protected].
  6. 6Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK. [email protected].
  7. 7Institute for Auditory Neuroscience and Inner Ear Lab, University Medical Center Göttingen, Göttingen, Germany. [email protected].
  8. 8Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Göttingen, Germany. [email protected].
  9. 9Collaborative Research Center 1690 (CRC 1690), University of Göttingen, Göttingen, Germany. [email protected].
  10. 10Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
  11. 11Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{torbati2026expanding,
  title = {{Expanding the genetic spectrum of inherited peripheral neuropathies in complex neurogenetic disorders using whole-exome sequencing.}},
  author = {Paria Najarzadeh Torbati and Reza Boostani and Mojtaba Safi and Najmeh Ahangari and Mohammad Doosti and Hasan Badpar and Mehran Beiraghi Toosi and Ehsan Ghayoor Karimiani and Barbara Vona},
  journal = {Neurogenetics},
  year = {2026},
  month = oct,
  doi = {10.1007/s10048-026-00952-w},
  url = {https://europepmc.org/article/MED/42955121},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Expanding the genetic spectrum of inherited peripheral neuropathies in complex neurogenetic disorders using whole-exome sequencing.
AU  - Paria Najarzadeh Torbati
AU  - Reza Boostani
AU  - Mojtaba Safi
AU  - Najmeh Ahangari
AU  - Mohammad Doosti
AU  - Hasan Badpar
AU  - Mehran Beiraghi Toosi
AU  - Ehsan Ghayoor Karimiani
AU  - Barbara Vona
PY  - 2026
DA  - 2026/10/29
JO  - Neurogenetics
DO  - 10.1007/s10048-026-00952-w
UR  - https://europepmc.org/article/MED/42955121
AB  - 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.
SN  - 1364-6745
SN  - 1364-6753
ER  -