Abstract
Intellectual disabilities (ID) and autism spectrum disorders (ASD) are characterized by extreme genetic and phenotypic heterogeneity. However, understanding this heterogeneity is difficult due to the intricate interplay among multiple interconnected genes, epigenetic factors, oxidative stress, and environmental factors. Employing next-generation sequencing (NGS), we revealed the genetic cause of ID and autistic traits in two patients from a consanguineous family followed by segregation analysis. Furthermore, in silico prediction methods and 3D modeling were conducted to predict the effect of the variants. To establish genotype–phenotype correlation, X-chromosome inactivation using Methylation-specific PCR and oxidative stress markers were also investigated. By analyzing the NGS data of the two patients, we identified a novel frameshift mutation c.2174_2177del (p.Thr725MetfsTer2) in the MAP7D3 gene inherited from their mother along with the functional BDNF Val66Met polymorphism inherited from their father. The 3D modeling demonstrated that the p.Thr725MetfsTer2 variant led to the loss of the C-terminal tail of the MAP7D3 protein. This change could destabilize its structure and impact kinesin-1’s binding to microtubules via an allosteric effect. Moreover, the analysis of oxidative stress biomarkers revealed an elevated oxidative stress in the two patients compared to the controls. To the best of our knowledge, this is the first report describing severe ID and autistic traits in familial cases with novel frameshift mutation c.2174_2177del in the MAP7D3 gene co-occurring with the functional polymorphism Val66M in the BDNF gene. Besides, our study underlines the importance of investigating combined genetic variations, X-chromosome inactivation (XCI) patterns, and oxidative stress markers for a better understanding of ID and autism etiology.
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Abbreviations
- ASD:
-
Autism spectrum disorder
- ID:
-
Intellectual disability
- MAP7D3:
-
MAP7 domain containing 3
- BDNF:
-
Brain-derived neurotrophic factor
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Acknowledgements
We would like to thank Mrs. Olfa Abida for participating in the X-inactivation analysis in this study.
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MK, FF, AT, and OA conceived and designed the study. MK, AT, JC, and AB, analyzed the data. MK and MM prepared the figures and/or tables. OJ and YG prepared the clinical data. FK, CT, and FF revised the final version of the manuscript. All the authors read and approved the final manuscript.
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The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the local ethic committee: The Regional Committee of the Protection of Persons, Sfax, Tunisia (CPP SUD reference number 0193/2019).
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Kharrat, M., Issa, A.B., Tlili, A. et al. A Novel Mutation in the MAP7D3 Gene in Two Siblings with Severe Intellectual Disability and Autistic Traits: Concurrent Assessment of BDNF Functional Polymorphism, X-Inactivation and Oxidative Stress to Explain Disease Severity. J Mol Neurosci 73, 853–864 (2023). https://doi.org/10.1007/s12031-023-02163-6
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DOI: https://doi.org/10.1007/s12031-023-02163-6