Table 3.

Studies on the role of MTHFR Gene C677T Polymorphism in ASDs risk.

No	Study	Type of Study	Sample Size	Age	Aim of Study	Study Outcome Parameters	Outcomes
1	Guo T et al., (2012) [52]	Population-based case-control study	n = 186 ASDs children vs. 186 control children	8.1 (±4.3) years old	Role of the MTHFR C677T polymorphism on the autism risk in the population	Frequency of genotype MTHFR 677TT in children	The frequency of genotype MTHFR 677TT in children with autism was significantly higher than those in controls. This study suggested that MTHFR C677T is a risk factor of autism in Chinese Han children [52].
2	Goin-Kochel RP et al., (2009) [53]	Exploratory genotype-phenotype correlations study	n = 147 ASDs children	7.9 years old	Potential differences among MTHFR genotypes for specific behaviors	Blood samples genotyped for the MTHFR 677C-T polymorphism	The results provide preliminary evidence supporting a relationship between MTHFR 677C-T genotype and specific behaviors among children with autism [53].
3	Santos PAC dos et al., (2010) [54]	Case-control study	n = 151 ASDs children vs. 100 healthy control children	<3 years old	Association between C677Tpolymorphism and ASDs	ADI-R criteria used for the evaluation of patient’s behavior genotype distribution of the MTHFR C667T polymorphism	The frequency of the T allele was 0.38 for the case group and 0.35 for the control group (p = 0.77). The genotypic distribution did not show significant differences between cases and controls (p = 0.72) nor association between the T allele and selected behaviors [54].
4	Mohammad NS et al., (2016) [55]	Case-control study	n = 138 ASDs children vs. 138 non-autistic children of matched age	(4.4±1.7) years old vs. (4.4±1.6) years old	Development of an artificial neural network (ANN) model from the data of 138 autistic and 138 non-autistic children using GCPII C1561T, SHMT1 C1420T, MTHFR C677T, MTR A2756G, and MTRR A66G as the predictors of autism risk	Genetic analyses:GCPII C1561T, SHMT1 C1420T, MTHFR C677T, MTR A2756G, and MTRR A66G as predictors of autism risk.Plasma homocysteine determination	Genetic polymorphisms of the folate pathway were moderate predictors of autism risk. MTHFR C677T and hyperhomocysteinemia have been identified as risk factors for autism worldwide. Synergistic interactions between MTHFR C677T and MTRR A66G increase homocysteine [55].
5	Ismail S et al., (2019) [56]	Case-control study	n = 78 ASDs children vs. 80matched healthy control children	3–6 years old	Investigate the association of MTHFR gene rs1801133 (C677T) variant among ASDs children	Full clinical and radiological examinations DNA genotyped for MTHFR genetic variant (C677T)	MTHFR (C677T) allele frequency was found to be higher significantly in ASDs cases compared with non-autistic children. Additionally, there was a higher distribution of combined CT + TT genotypes among autistic patients with consanguinity and family history of psychological disease [56].
6	Zhang Z et al., (2018) [57]	Case-control study	n = 201 ASDs children vs. 200 healthy control children	-	Association between childhood ASDs and single-nucleotide polymorphisms (SNPs) in genes involved with vitamin B12 and folate metabolism	Genotypes of transcobalamin 2 (TCN2) rs1801198, methionine synthase (MTR) rs1805087, methionine synthase reductase (MTRR) rs1801394, and methylene tetrahydrofolate reductase (MTHFR) rs1801133 were examined	Results showed no association of all examined single-nucleotide polymorphisms SNPs with childhood ASDs and its severity [57].
7	Sener EF et al., (2014) [58]	Cohort study	n = 98 ASDs children vs. 70 age and sex-matched non-autistic children	≦3 years old	Investigate the possible effect of C677T polymorphisms in a population cohort	DNA tested for MTHFR C677T polymorphism	MTHFR 677T-allele frequency was found to be higher in autistic children compared with non-autistic children, but it was not found statistically significant [58].
8	Mohammad NS et al., (2009) [59]	Population study	n = 138 ASDs children vs. 138 age and sex matched nonautistic children	2–10 years old	Investigate whether genetic polymorphisms are the underlying causes for aberrations in folate pathway reported in autistic children	DNA tested for five genetic polymorphisms: cytosolic serine hydroxyl methyl transferase (SHMT1 C1420T), methylene tetrahydrofolate reductase (MTHFR C677T, and MTHFR A1298C), methionine synthase reductase (MTRR A66G), methionine synthase (MS A2756G)	MTHFR C677T is a risk factor, whereas MTRR A66G and SHMT C1420T polymorphismsreduce the risk for autism. MTHFR A1298C acts additively in increasing the risk for autism [59].
9	El-Baz F et al., (2017) [60]	Case-control study	n = 31 ASDs children vs. 39 children normal control group	4.5 ± 2 years old	Identification of C677T and 1298AC polymorphic genotypes of MTHFR gene among a sample of children with autism	Identification of C677T and 1298AC polymorphic genotypes of MTHFR gene	There is a significant association between severity and occurrence of autism with MTHFR gene polymorphisms C677T and A1298C. Further studies are needed on a larger scale to explore other gene polymorphisms that may be associated with autism to correlate the genetic basis of autism [60].
10	James SJ et al., (2010) [61]	Population-basedcase-control study	n = 529 case-parent triosvs. 566 TD controls	3–10 years old	Investigate the frequency of common functional polymorphisms in the folate pathway	Allele frequencies of MTHFR C677T, MTHFR A1298C, TCII C776G, or MTRR A66G among mothers, fathers, or affected child compared to population controls. Determination of percent 5-methylcystosine/ total cytosine in DNA plasma transmethylation metabolites genetic relative risk and likelihood ratio test, transmission disequilibrium test, maternal plasma transmethylation metabolites and plasma folate concentrationslobal DNA methylation density and RFC1genotype association among Arkansas mothers	The results showed a significant increase in the reduced folate carrier (RFC1) G allele frequency among case mothers but not among fathers or affected children. Subsequent log linear analysis of the RFC1 A80G genotype within family trios revealed that the maternal G allele was associated with a significant increase in risk of autism, whereas the inherited genotype of the child was not.Results suggest that the maternal genetics/epigenetics may influence fetal predisposition to autism [61].