Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families

Abstract

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder, characterized by lower-limb spasticity and weakness. To date, more than 82 loci/genes (SPG1-SPG82) have been identified that contribute to the cause of HSP. Despite the use of next-generation sequencing-based methods, genetic-analysis has failed in the finding of causative genes in more than 50% of HSP patients, indicating a more significant heterogeneity and absence of a given phenotype-genotype correlation. Here, we performed whole-exome sequencing (WES) to identify HSP-causing genes in three unrelated-Iranian probands. Candidate variants were detected and confirmed in the probands and co-segregated in the family members. The phenotypic data gathered and compared with earlier cases with the same sub-types of disease. Three novel homozygous variants, c.978delT; p.Q327Kfs*39, c.A1208G; p.D403G and c.3811delT; p.S1271Lfs*44, in known HSP-causing genes including ENTPD1, CYP7B1, and ZFYVE26 were identified, respectively. Intra and interfamilial clinical variability were observed among affected individuals. Mutations in CYP7B1 and ZFYVE26 are relatively common causes of HSP and associated with SPG5A and SPG15, respectively. However, mutations in ENTPD1 are related to SPG64 which is an ultra-rare form of HSP. The research affirmed more complexities of phenotypic manifestations and allelic heterogeneity in HSP. Due to these complexities, it is not feasible to show a clear phenotype-genotype correlation in HSP cases. Identification of more families with mutations in HSP-causing genes may help the establishment of this correlation, further understanding of the molecular basis of the disease, and would provide an opportunity for genetic-counseling in these families.

Keywords:

• Hereditary spastic paraplegia (HSP)
• CYP7B1 (SPG5A)
• ENTPD1 (SPG64)
• ZFYVE26 (SPG15)
• Whole-exome sequencing (WES)

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Acknowledgements

We acknowledge the Iran National Institute for Medical Research Development (NIMAD; grant number 963846) and the University of Social Welfare and Rehabilitation Sciences for funding the research and thank the patients and their family members for participating in the study.

Author contributions

Mahdieh Pashaei, Atefeh Davarzani, and Reza Hajati: DNA extraction, analysis of exome sequencing data, primer design, mutation screening of candidate variants; Farzaneh Larti: Advisors of MP; Babak Zamani and Shahriar Nafissi: clinical evaluations and editing of manuscript; Yalda Nilipour: performing muscle biopsy, Mohammad Rohani: clinical evaluations, writing and editing of manuscript; Afagh Alavi: designed and supervised the research, writing of the manuscript. All authors read and approved the final version of manuscript.

Disclosure statement

The authors have no conflicts of interest to declare.

Data availability statement

The data are available on request from the corresponding author.

Additional information

Funding

This work was supported by The National Institute for Medical Research Development [NIMAD; grant number 963846] and University of Social Welfare and Rehabilitation Sciences.