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.

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 (χ = 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 overlapping 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.