Human Gene Module / Chromosome 1 / MTHFR

MTHFRmethylenetetrahydrofolate reductase (NAD(P)H)

Score
4
Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
10 / 16
Rare Variants / Common Variants
2 / 11
Aliases
MTHFR, 5, 10-methylenetetrahydrofolate reductase (NADPH)
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
1p36.22
Associated Disorders
ID
Relevance 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.

Reports related to MTHFR (16 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 fro... 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 Highly Cited A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Weisberg I , et al. (1998) No -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
G>A p.Leu323Phe missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.[199C>T];[199C>T] p.[Pro67Ser];[Pro67Ser] missense_variant;missense_variant Familial Both parents Multiplex 28097321 Reuter MS , et al. (2017)
Common Variants   (11)
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;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
4

Minimal Evidence

4

Score Delta: Score remained at 4.3

4

Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.

7/1/2017
4
icon
4

Score remained at 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
4
icon
4

Score remained at 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
4
icon
4

Score remained at 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).

7/1/2014
No data
icon
4

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
No data
icon
4

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]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 2.4551580926621E-7

Ranking 15455/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.9438721297787

Ranking 15855/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 44.75

Ranking 43/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.42176254097808

Ranking 1215/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with MTHFR(1 CNVs)
1p36.22 14 Deletion-Duplication 26  /  111
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