Expanding the genetic and clinical landscapes of hereditary spastic paraplegia (HSP): a cohort study of 103 families

Atefeh Davarzani; Moez Ravanbod; Aida Ghasemi; Mahsa Mohammadi; Mohammad Rohani; Shahriar Nafissi; Payman Jamali; Hossein Najmabadi; Farzad Fatehi; Shahryar Alavi; Zahra Firoozfar; Fariba Zemorshidi; Mohammad Reza Habibi-Kavashkohie; Afagh Alavi

doi:10.1186/s13023-026-04373-8

Expanding the genetic and clinical landscapes of hereditary spastic paraplegia (HSP): a cohort study of 103 families

Orphanet J Rare Dis. 2026 May 12. doi: 10.1186/s13023-026-04373-8. Online ahead of print.

Authors

Atefeh Davarzani¹, Moez Ravanbod¹, Aida Ghasemi², Mahsa Mohammadi¹, Mohammad Rohani³, Shahriar Nafissi^{2

4}, Payman Jamali⁵, Hossein Najmabadi^{1

6}, Farzad Fatehi^{2

4

7}, Shahryar Alavi^{8

9}, Zahra Firoozfar^{8

10}, Fariba Zemorshidi¹¹, Mohammad Reza Habibi-Kavashkohie¹², Afagh Alavi^{13

14}

Affiliations

¹ Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
² Neuromuscular Research Center, Tehran University of Medical Sciences, Tehran, Iran.
³ Department of Neurology, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran.
⁴ Neurology Department, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
⁵ The Genetic Counseling Center, Shahroud Welfare Organization, Shahroud, Iran.
⁶ Kariminejad-Najmabadi Pathology & Genetic Center, Tehran, Iran.
⁷ Visiting Academic, Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
⁸ Palindrome, Isfahan, Iran.
⁹ Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹⁰ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹¹ Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
¹² CHU Sainte Justine Research Center, University of Montreal, Montréal, Canada.
¹³ Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. afaghalavi@gmail.com.
¹⁴ Neuromuscular Research Center, Tehran University of Medical Sciences, Tehran, Iran. afaghalavi@gmail.com.

PMID: 42120987
DOI: 10.1186/s13023-026-04373-8

Abstract

Background: Hereditary spastic paraplegia (HSP) refers to a heterogeneous group of genetic disorders with more than 90 causative genes. Clinically, HSP is classified into pure and complicated forms. Pure forms are characterized primarily by lower-limb spasticity and weakness, whereas complicated forms include additional neurological or non-neurological symptoms alongside spasticity and weakness. We aimed to characterize the clinical and genetic landscapes of HSP in an Iranian cohort. Whole-exome sequencing (WES) was performed on 103 unrelated clinically suspected HSP probands. Multiple ligation-dependent probe amplification (MLPA) was performed to validate identified copy number variants (CNVs) in two probands.

Results: 71 pathogenic/likely pathogenic and VUS variants were identified in 81 probands; total genetically solved probands: 78.6%. Among these solved cases, 64 probands harbored variants in known HSP genes, 14 had variants in other neuromuscular/neurodegenerative-related genes, and the remaining 3 probands carried variants in four novel candidate genes including NMNAT1, SEMA3A, KCNJ14, and EMP3. Among all 71 identified genomic variants, two were CNVs and one was a trinucleotide repeat expansion. Taken together, these variants were located in 37 genes; 21 of these genes have been previously implicated in HSP, and four common HSP subtypes (SPG11, SPG4, SPG7, and SPG15) accounted for ~40% of our cohort.

Conclusions: This study demonstrates significant clinical and genetic heterogeneity of HSP within our cohort. In addition to variants in 21 known HSP-related genes, we identified variants in 14 genes related to other neurological disorders -highlighting shared biological pathways- as well as variants in four novel candidate genes. Notably, a genetic diagnosis could not be established in 22 probands, underscoring that additional, as yet unidentified genes likely contribute to HSP pathogenesis.

Keywords: Genetic heterogeneity; Hereditary spastic paraplegia (HSP); SPG11; SPG4; Whole-exome sequencing (WES).