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Novel and known minor alleles of CNTNAP2 gene variants are associated with comorbidity of intellectual disability and epilepsy phenotypes: a case–control association study reveals potential biomarkers

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Abstract

Background

Neurodevelopmental disorders are heterogeneous due to underlying multiple shared genetic pathways and risk factors. Intellectual disability, epilepsy and autism spectrum disorder phenotypes overlap which indicates the diverse effects of common genes. Recent studies suggested the probable contribution of CNTNAP2 gene polymorphisms to the comorbidity of these neurological conditions.

Methods and results

This study was conducted to investigate the role of CNTNAP2 polymorphisms rs147815978 (G>T) and rs2710102 (A>G) as a risk factor for comorbidity of intellectual disability and epilepsy in a group of 345 individuals including 170 patients and 175 healthy controls recruited from various ethnic groups of Pakistani population. Our case–control study group was genotyped by tetra primer ARMS-PCR technique and results were analysed to know the effects of CNTNAP2 rs147815978 (G>T) and rs2710102 (A>G) polymorphisms in the group. The frequency of risk allele T (rs147815978) and risk allele G (rs2710102) for homozygous recessive genotypes (TT/GG) in our study group was 36.47% while odds ratios for risk allele T (rs147815978) was 5.45 (3.90–7.61: 95% CI, P = 0.000) and that for risk allele G (rs2710102) was 2.39 (1.76–3.24: 95% CI, P = 0.0001). Homozygous recessive genotypes (TT/GG) appeared only in cases and not in control group which indicated these as suspected risk genotypes and the significant association (p < 0.05%) of CNTNAP2 gene polymorphisms rs147815978 (G>T) and rs2710102 (A>G) with co-occurrence of intellectual disability and epilepsy phenotypes in our study group which is in HWE (χ2 = 174, P < 0.0001). Logistic regression analysis shows additive (p < 0.0001) and multiplicative (p < 0.001) models which confirms significant association of both the polymorphisms in our data, which are closely located on same haplotype (D′ = − 0.168).

Conclusions

We propose that CNTNAP2 rs147815978 (G>T) and rs2710102 (A>G) polymorphisms are possible risk loci for overlap** neurodevelopmental disorders in Pakistani population. We propose the role of a previously reported common SNP rs2710102 (A>G) with a rarely reported novel SNP rs147815978 (G>T) for CNTNAP2 gene association with neurodevelopmental disorders in our data. Our study has expanded the knowledge of CNTNAP2 gene polymorphisms as probable biomarkers for susceptibility of co-occurrence of intellectual disability and epilepsy phenotypes in Pakistani population. We hope that our study will open new horizons of CNTNAP2 gene variants research to cure the neurological conditions in Pakistani population where consanguinity is a tradition and prevalence of neurodevelopmental disorders has increased from 1 to 2% during last 5 years.

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Data availability

The data supporting this study findings is available on request from the authors.

Abbreviations

BBH:

Benazir Bhutto hospital

OPD:

Outpatient door

NDD:

Neurodevelopmental disorders

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Acknowledgements

We are thankful to all the patients for participating in the study. Special thanks to Holy Family Hospital and BBH for providing diagnostic facilities to the patients. Highly indebted to Translational Genomics Lab COMSATS University Islamabad for providing sample storage, DNA extraction, primer designing and optimization, ARMS-PCR facilities. Special thanks to IBGE, KRL for providing data analysis support.

Funding

The study has been conducted through the funds provided by grant # NRPU Project No.16281, Higher Education Commission Pakistan, awarded to Dr. Zehra Agha from Translational Genomics Lab, COMSATS University, Islamabad. 

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Authors and Affiliations

  1. Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan

    Behjat Ul Mudassir & Zehra Agha

  2. Department of Psychiatry, State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14203, USA

    Zehra Agha

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  1. Behjat Ul Mudassir
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Contributions

BM has designed the study, collected blood samples, performed experimental work, and written the first draft of the manuscript. ZA has supervised the study and provided data analysis support for the final draft of the manuscript.

Corresponding author

Correspondence to Zehra Agha.

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Authors declare no competing interests.

Ethical approval

This study was approved by the Institutional Review Board of Department of Biosciences, The COMSATS University, Islamabad (CUI-Reg/Notif-1616/18/2/27 dated 5th June 2018).

Informed consent

Written informed consent for clinical and genetic testing, publication of information was provided by attendants of patients. Diagnosis was carried out in collaboration with the neurological consultants in their OPD clinics at Holy family Hospital and BBH, Rawalpindi.

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Ul Mudassir, B., Agha, Z. Novel and known minor alleles of CNTNAP2 gene variants are associated with comorbidity of intellectual disability and epilepsy phenotypes: a case–control association study reveals potential biomarkers. Mol Biol Rep 51, 276 (2024). https://doi.org/10.1007/s11033-023-09176-9

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