Abstract
Hereditary neurological disorders (HNDs) are a clinically and genetically heterogeneous group of disorders. These disorders arise from the impaired function of the central or peripheral nervous system due to aberrant electrical impulses. More than 600 various neurological disorders, exhibiting a wide spectrum of overlapping clinical presentations depending on the organ(s) involved, have been documented. Owing to this clinical heterogeneity, diagnosing these disorders has been a challenge for both clinicians and geneticists and a large number of patients are either misdiagnosed or remain entirely undiagnosed. Contribution of genetics to neurological disorders has been recognized since long; however, the complete picture of the underlying molecular bases are under-explored. The aim of this study was to accurately diagnose 11 unrelated Pakistani families with various HNDs deploying NGS as a first step approach. Using exome sequencing and gene panel sequencing, we successfully identified disease-causing genomic variants these families. We report four novel variants, one each in, ECEL1, NALCN, TBR1 and PIGP in four of the pedigrees. In the rest of the seven families, we found five previously reported pathogenic variants in POGZ, FA2H, PLA2G6 and CYP27A1. Of these, three families segregate a homozygous 18 bp in-frame deletion of FA2H, indicating a likely founder mutation segregating in Pakistani population. Genotyping for this mutation can help low-cost population wide screening in the corresponding regions of the country. Our findings not only expand the existing repertoire of mutational spectrum underlying neurological disorders but will also help in genetic testing of individuals with HNDs in other populations.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors are grateful to the patients and their families for taking part in this study.
Funding
This work was supported by grants from Higher Education Commission of Pakistan (NRPU 20-12107 and NRPU 7451), National Natural Science Foundation of China (31625015, 31521003 and 32100480), China Postdoctoral Science Foundation (2020TQ0072), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and the 111 Project (B13016). The aforementioned grants covered the costs of materials required for DNA extraction and expenses of whole exome sequencing and Sanger sequencing. AK was supported by HEC’s IRSIP fellowship.
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1000 Genomes Project, https://www.internationalgenome.org. Genome Aggregation Database (gnomAD), http://gnomad.broadinstitute.org. The Human Gene Mutation Database (HGMD), http://www.hgmd.cf.ac.uk.
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Khan, A., Tian, S., Tariq, M. et al. NGS-driven molecular diagnosis of heterogeneous hereditary neurological disorders reveals novel and known variants in disease-causing genes. Mol Genet Genomics 297, 1601–1613 (2022). https://doi.org/10.1007/s00438-022-01945-8
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DOI: https://doi.org/10.1007/s00438-022-01945-8