Genetic and in silico analysis of Indian sporadic young onset patient with amyotrophic lateral sclerosis

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is an old onset devastating neurodegenerative disorder. Young-onset ALS cases especially sporadic ones who are between 25 and 45 years are rarely affected by the disease. Despite the identification of numerous candidate genes associated with ALS, the etiology of the disease remains elusive due to extreme genetic and phenotypic variability. The advent of affordable whole exome sequencing (WES) has opened new avenues for unraveling the disease’s pathophysiology better. Methods and results: We aimed to determine the genetic basis of an Indian-origin, young onset sporadic ALS patient with very rapid deterioration of the disease course without any cognitive decline who was screened for mutations in major ALS candidate genes by WES. Variants detected were reconfirmed by Sanger sequencing. The clinicopathological features were investigated and two heterozygous missense variants were identified: R452W, not previously associated with ALS, present in one of the four conserved C terminal domains in ANXA11 and R208W in SIGMAR1, respectively. Both of these variants were predicted to be damaging by pathogenicity prediction tools and various in silico methods. Conclusion: Our study revealed two potentially pathogenic variants in two ALS candidate genes. The genetic makeup of ALS patients from India has been the subject of a few prior studies, but none of them examined ANXA11 and SIGMAR1 genes so far. These results establish the framework for additional research into the pathogenic processes behind these variations that result in sporadic ALS disease and further our understanding of the genetic makeup of Indian ALS patients.

Keywords:

• Amyotrophic lateral sclerosis
• motor neuron disease
• sporadic ALS
• genetics
• ANXA11 mutation
• SIGMAR1 mutation
• Indian ALS patient

Acknowledgements

The authors are grateful to the patient and his family members for their contribution to this study. The authors wish to thank Ms. Pooja Sharma, Research Scholar, CSIR-IGIB, New Delhi, India for providing help with the repeat expansion work.

Author contributions

PD: conceptualization, methodology, supervision, resources, and reviewing. SRC: conceptualization, methodology, investigation, formal analysis, and writing-original draft preparation. DJ: patient sample collection and investigation. VKS: software and formal analysis. MF: resources and investigation.

Ethics statement

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Institute of Science, Banaras Hindu University (Ref. No.: I.Sc/ECM-XIV/2022-23/).

Consent form

Patient and his family agreed to take part in this research through written informed consent form.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Data availability statement

Data will be made available upon request.

Code availability statement

Not applicable.

Additional information

Funding

Not applicable. However, the first author acknowledges Department of Science and Technology (DST), India for providing Junior Research Fellowship (JRF) & Senior Research Fellowship (SRF).