MTHFRmethylenetetrahydrofolate reductase (NAD(P)H)
Autism Reports / Total Reports
17 / 24Rare Variants / Common Variants
8 / 12Aliases
MTHFR, 5, 10-methylenetetrahydrofolate reductase (NADPH)Associated Syndromes
-Chromosome Band
1p36.22Associated Disorders
IDRelevance to Autism
Several studies have found genetic association between the MTHFR gene and autism in Caucasian and Indian population cohorts as well as AGRE cohorts. However, another study found no genetic association between the MTHFR gene and autism in a Brazilian population cohort. Separately, a study showed that the MTHFR C677T variant is associated with greater depressed mood during pregnancy.
Molecular Function
The encoded protein catalyzes the conversion of 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine.
External Links
SFARI Genomic Platforms
Reports related to MTHFR (24 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Highly Cited | MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis | Klerk M , et al. (2002) | No | - |
| 2 | Primary | Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism | James SJ , et al. (2006) | Yes | - |
| 3 | Positive Association | Aberrations in folate metabolic pathway and altered susceptibility to autism | Mohammad NS , et al. (2009) | Yes | - |
| 4 | Positive Association | The MTHFR 677C-->T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations | Goin-Kochel RP , et al. (2009) | Yes | - |
| 5 | Negative Association | MTHFR C677T is not a risk factor for autism spectrum disorders in South Brazil | dos Santos PA , et al. (2010) | Yes | - |
| 6 | Recent Recommendation | Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth | Devlin AM , et al. (2010) | No | - |
| 7 | Recent Recommendation | Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice | Levav-Rabkin T , et al. (2010) | No | - |
| 8 | Positive Association | Population- and family-based studies associate the MTHFR gene with idiopathic autism in simplex families | Liu X , et al. (2010) | Yes | - |
| 9 | Recent Recommendation | Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study | Schmidt RJ , et al. (2012) | No | - |
| 10 | Positive Association | Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population | Guo T , et al. (2012) | Yes | - |
| 11 | Positive Association | Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis | Pu D , et al. (2013) | Yes | - |
| 12 | Recent Recommendation | Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility | Rai V (2016) | Yes | - |
| 13 | Support | Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders | Reuter MS , et al. (2017) | No | ID, microcephaly |
| 14 | Support | Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder | Lim ET , et al. (2017) | Yes | - |
| 15 | Positive Association | Study of C677T variant of methylene tetrahydrofolate reductase gene in autistic spectrum disorder Egyptian children | Ismail S , et al. (2019) | Yes | - |
| 16 | Positive association | Association of MTHFR 677C>T and 1298A>C polymorphisms with susceptibility to autism: A systematic review and meta-analysis | Sadeghiyeh T , et al. (2019) | Yes | - |
| 17 | Support | Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression | Yin J et al. (2020) | Yes | Developmental regression |
| 18 | Support | - | Woodbury-Smith M et al. (2022) | Yes | - |
| 19 | Support | - | Zhou X et al. (2022) | Yes | - |
| 20 | Support | - | Khan S et al. (2023) | Yes | - |
| 21 | Support | - | Sadigurschi N et al. (2023) | Yes | - |
| 22 | Support | - | Bartolomaeus T et al. (2023) | No | - |
| 23 | Support | - | Omri Bar et al. (2024) | Yes | ADHD, ID, epilepsy/seizures |
| 24 | Highly Cited | A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity | Weisberg I , et al. (1998) | No | - |
Rare Variants (8)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.130A>T | p.Asn44Tyr | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.136C>T | p.Arg46Trp | missense_variant | Unknown | - | Unknown | 32722525 | Yin J et al. (2020) | |
| c.1090C>T | p.Leu364Phe | missense_variant | De novo | - | Simplex | 28714951 | Lim ET , et al. (2017) | |
| c.776T>C | p.Val259Ala | missense_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) | |
| c.101C>T | p.Thr34Ile | missense_variant | Familial | Maternal | Simplex | 38256266 | Omri Bar et al. (2024) | |
| c.1409A>T | p.Glu470Val | missense_variant | Familial | Paternal | Simplex | 38256266 | Omri Bar et al. (2024) | |
| c.199C>T | p.Pro67Ser | missense_variant | Familial | Both parents | Multiplex | 28097321 | Reuter MS , et al. (2017) | |
| c.199C>T | p.Pro67Ser | missense_variant | Familial | Both parents | Multiplex | 37460657 | Bartolomaeus T et al. (2023) |
Common Variants (12)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val | missense_variant | - | - | - | 31033224 | Ismail S , et al. (2019) | |
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val | missense_variant | - | - | - | 31614268 | Sadeghiyeh T , et al. (2019) | |
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val | missense_variant | - | - | - | 23653228 | Pu D , et al. (2013) | |
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val | missense_variant | - | - | - | 21069446 | Liu X , et al. (2010) | |
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val | missense_variant | - | - | - | 22775456 | Guo T , et al. (2012) | |
| c.1286A>C;c.1409A>C;c.1355A>C;c.1040A>C | p.Glu429Ala;p.Glu470Ala;p.Glu452Ala;p.Glu347Ala | missense_variant | - | - | - | 23653228 | Pu D , et al. (2013) | |
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val | missense_variant | - | - | - | 16917939 | James SJ , et al. (2006) | |
| c.1286A>C;c.1409A>C;c.1355A>C;c.1040A>C | p.Glu429Ala;p.Glu470Ala;p.Glu452Ala;p.Glu347Ala | missense_variant | - | - | - | 21069446 | Liu X , et al. (2010) | |
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val | missense_variant | - | - | - | 20808944 | Devlin AM , et al. (2010) | |
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val | missense_variant | - | - | - | 19440165 | Mohammad NS , et al. (2009) | |
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val | missense_variant | - | - | - | 19455642 | Goin-Kochel RP , et al. (2009) | |
| c.665C>T;c.788C>T;c.734C>T;c.419C>T | p.Ala222Val | missense_variant | - | - | - | 26956130 | Rai V (2016) |
SFARI Gene score
Strong Candidate
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). In a study involving 186 cases and 186 controls in a Chinese Han population, a higher frequency of the 677TT genotype was found compared to controls (PMID 22775456). A meta-analysis of 8 case-control studies involving 1672 ASD cases and 6760 controls showed that the C677T polymorphism was associated with ASD risk in multiple comparison models (Pu et al., 2013). Association of the C677T polymorphism with autism was also observed using multiple genetic models in a larger meta-analysis involving the 8 case-control studies used in Pu et al., 2013 and an additional 5 case-control studies (Rai et al., 2016).
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
4/1/2022
Decreased from 3 to 2
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). In a study involving 186 cases and 186 controls in a Chinese Han population, a higher frequency of the 677TT genotype was found compared to controls (PMID 22775456). A meta-analysis of 8 case-control studies involving 1672 ASD cases and 6760 controls showed that the C677T polymorphism was associated with ASD risk in multiple comparison models (Pu et al., 2013). Association of the C677T polymorphism with autism was also observed using multiple genetic models in a larger meta-analysis involving the 8 case-control studies used in Pu et al., 2013 and an additional 5 case-control studies (Rai et al., 2016).
7/1/2020
Decreased from 3 to 3
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). In a study involving 186 cases and 186 controls in a Chinese Han population, a higher frequency of the 677TT genotype was found compared to controls (PMID 22775456). A meta-analysis of 8 case-control studies involving 1672 ASD cases and 6760 controls showed that the C677T polymorphism was associated with ASD risk in multiple comparison models (Pu et al., 2013). Association of the C677T polymorphism with autism was also observed using multiple genetic models in a larger meta-analysis involving the 8 case-control studies used in Pu et al., 2013 and an additional 5 case-control studies (Rai et al., 2016).
1/1/2020
Decreased from 3 to 3
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). In a study involving 186 cases and 186 controls in a Chinese Han population, a higher frequency of the 677TT genotype was found compared to controls (PMID 22775456). A meta-analysis of 8 case-control studies involving 1672 ASD cases and 6760 controls showed that the C677T polymorphism was associated with ASD risk in multiple comparison models (Pu et al., 2013). Association of the C677T polymorphism with autism was also observed using multiple genetic models in a larger meta-analysis involving the 8 case-control studies used in Pu et al., 2013 and an additional 5 case-control studies (Rai et al., 2016).
10/1/2019
Decreased from 4 to 3
New Scoring Scheme
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). In a study involving 186 cases and 186 controls in a Chinese Han population, a higher frequency of the 677TT genotype was found compared to controls (PMID 22775456). A meta-analysis of 8 case-control studies involving 1672 ASD cases and 6760 controls showed that the C677T polymorphism was associated with ASD risk in multiple comparison models (Pu et al., 2013). Association of the C677T polymorphism with autism was also observed using multiple genetic models in a larger meta-analysis involving the 8 case-control studies used in Pu et al., 2013 and an additional 5 case-control studies (Rai et al., 2016).
Reports Added
[New Scoring Scheme]4/1/2019
Decreased from 4 to 4
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). In a study involving 186 cases and 186 controls in a Chinese Han population, a higher frequency of the 677TT genotype was found compared to controls (PMID 22775456). A meta-analysis of 8 case-control studies involving 1672 ASD cases and 6760 controls showed that the C677T polymorphism was associated with ASD risk in multiple comparison models (Pu et al., 2013). Association of the C677T polymorphism with autism was also observed using multiple genetic models in a larger meta-analysis involving the 8 case-control studies used in Pu et al., 2013 and an additional 5 case-control studies (Rai et al., 2016).
7/1/2017
Decreased from 4 to 4
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). In a study involving 186 cases and 186 controls in a Chinese Han population, a higher frequency of the 677TT genotype was found compared to controls (PMID 22775456). A meta-analysis of 8 case-control studies involving 1672 ASD cases and 6760 controls showed that the C677T polymorphism was associated with ASD risk in multiple comparison models (Pu et al., 2013). Association of the C677T polymorphism with autism was also observed using multiple genetic models in a larger meta-analysis involving the 8 case-control studies used in Pu et al., 2013 and an additional 5 case-control studies (Rai et al., 2016).
1/1/2017
Decreased from 4 to 4
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). In a study involving 186 cases and 186 controls in a Chinese Han population, a higher frequency of the 677TT genotype was found compared to controls (PMID 22775456). A meta-analysis of 8 case-control studies involving 1672 ASD cases and 6760 controls showed that the C677T polymorphism was associated with ASD risk in multiple comparison models (Pu et al., 2013). Association of the C677T polymorphism with autism was also observed using multiple genetic models in a larger meta-analysis involving the 8 case-control studies used in Pu et al., 2013 and an additional 5 case-control studies (Rai et al., 2016).
4/1/2016
Decreased from 4 to 4
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). In a study involving 186 cases and 186 controls in a Chinese Han population, a higher frequency of the 677TT genotype was found compared to controls (PMID 22775456). A meta-analysis of 8 case-control studies involving 1672 ASD cases and 6760 controls showed that the C677T polymorphism was associated with ASD risk in multiple comparison models (Pu et al., 2013). Association of the C677T polymorphism with autism was also observed using multiple genetic models in a larger meta-analysis involving the 8 case-control studies used in Pu et al., 2013 and an additional 5 case-control studies (Rai et al., 2016).
Reports Added
[Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.2006] [Aberrations in folate metabolic pathway and altered susceptibility to autism.2009] [The MTHFR 677C-->T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations.2009] [MTHFR C677T is not a risk factor for autism spectrum disorders in South Brazil.2010] [Population- and family-based studies associate the MTHFR gene with idiopathic autism in simplex families.2010] [Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population.2012] [A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.1998] [MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis.2002] [Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth.2010] [Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice.2010] [Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks fro...2012] [Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility.2016] [Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.2013]7/1/2014
Increased from No data to 4
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). And, finally, in a study involving 186 cases and186 controls in a Chinese Han population, a higher frequency of the 677TT geneotype was found compared to controls (PMID 22775456).
4/1/2014
Increased from No data to 4
Description
A genotype-phenotype study in an AGRE cohort found that the CT or TT genotype was associated with worse direct gaze, complex body movements, self-injury and overactivity (OR 2.1-2.7) (PMID 19455642). However, no association was found with the T allele and ASD (PMID 20440228). In a study of 205 simplex and 307 multiplex families, the 677T allele was more frequent in cases, the 677T-1298A haplotype and the 677TT/1298AA genotype were more frequent in simplex cases compared to controls (but not multiplex) (PMID 21069446). And, finally, in a study involving 186 cases and186 controls in a Chinese Han population, a higher frequency of the 677TT geneotype was found compared to controls (PMID 22775456).
Krishnan Probability Score
Score 0.40620812261057
Ranking 23123/25841 scored genes
[Show Scoring Methodology]
ExAC Score
Score 2.4551580926621E-7
Ranking 15455/18225 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.9438721297787
Ranking 15855/18665 scored genes
[Show Scoring Methodology]
Larsen Cumulative Evidence Score
Score 44.75
Ranking 43/461 scored genes
[Show Scoring Methodology]
Zhang D Score
Score 0.42176254097808
Ranking 1215/20870 scored genes
[Show Scoring Methodology]