MTHFR
Homo sapiens
Gene Name: methylenetetrahydrofolate reductase (NAD(P)H)
Aliases: 5,10-methylenetetrahydrofolate reductase (NADPH)
Chromosome No: 1
Chromosome Band: 1p36.22
Genetic Category: Genetic Association-Syndromic-Rare single gene variant-Functional
Associated Syndrome(s): Homocystinuria due to MTHFR deficiency
Aliases: 5,10-methylenetetrahydrofolate reductase (NADPH)
Chromosome No: 1
Chromosome Band: 1p36.22
Genetic Category: Genetic Association-Syndromic-Rare single gene variant-Functional
Associated Syndrome(s): Homocystinuria due to MTHFR deficiency
Summary Statistics:
ASD Reports: 24
Recent Reports: 4
Annotated variants: 20
Associated CNVs: 14
Evidence score: 2
ASD Reports: 24
Recent Reports: 4
Annotated variants: 20
Associated CNVs: 14
Evidence score: 2
Gene Score: 4
Associated Disorders: |
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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.
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.
ASD
Positive Association
Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population.
ASD
Positive Association
Population- and family-based studies associate the MTHFR gene with idiopathic autism in simplex families.
ASD
Positive Association
The MTHFR 677C-->T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations.
ASD
Positive Association
Aberrations in folate metabolic pathway and altered susceptibility to autism.
ASD
Positive association
Association of MTHFR 677C>T and 1298A>C polymorphisms with susceptibility to autism: A systematic review and meta-analysis.
ASD
Positive Association
Study of C677T variant of methylene tetrahydrofolate reductase gene in autistic spectrum disorder Egyptian children.
ASD
Positive Association
Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.
ASD
Negative Association
MTHFR C677T is not a risk factor for autism spectrum disorders in South Brazil.
ASD
Support
Reanalysis of Trio Whole-Genome Sequencing Data Doubles the Yield in Autism Spectrum Disorder: De Novo Variants Present in Half
ASD
ADHD, ID, epilepsy/seizures
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.
Homocystinuria due to MTHFR deficiency
ID, microcephaly
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression
ASD
Developmental regression
Highly Cited
A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.
Highly Cited
MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis.
Recent Recommendation
Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility.
ASD
Recent Recommendation
Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks fro...
Recent Recommendation
Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice.
Recent Recommendation
Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth.
Rare
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
GEN163R001a
missense_variant
c.199C>T
p.Pro67Ser
Familial
Both parents
Multiplex
GEN163R006a
missense_variant
c.199C>T
p.Pro67Ser
Familial
Both parents
Multiplex
Common
Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
GEN163C001
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val
Indian
Discovery
GEN163C002
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val
North American-Caucasian, AGRE
Replication
GEN163C003
missense_variant
rs1801131
c.1286A>C;c.1409A>C;c.1355A>C;c.1040A>C
p.Glu429Ala;p.Glu470Ala;p.Glu452Ala;p.Glu347Ala
North American-Caucasian, AGRE
Discovery
GEN163C004
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val
AGRE
Replication
GEN163C005
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val
AGRE
Discovery
GEN163C006
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val
97% Caucasian
Replication
GEN163C007
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val
Chinese Han (186 children with autism, 186 controls)
Replication
GEN163C008
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val;p.Ala263Val;p.Ala245Val;p.Ala140Val
Case-control meta-analysis consisting of 8 studies involving 1672 ASD cases and 6760 controls
Meta-analysis
GEN163C009
missense_variant
rs1801131
c.1286A>C;c.1409A>C;c.1355A>C;c.1040A>C
p.Glu429Ala;p.Glu470Ala;p.Glu452Ala;p.Glu347Ala
Case-control meta-analysis consisting of 8 studies involving 1672 ASD cases and 6760 controls
Meta-analysis
GEN163C010
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val
Case-control meta-analysis consisting of 13 studies (9 from Caucasian population, 4 from Asian population) comprising 1978 cases and 7257 controls. 8 of these studies were used in the C677T meta-analysis in PMID 23653228.
Meta-analysis
GEN163C011
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val
78autisticchildren, 80 matched healthy control children (Egypt)
Replication
GEN163C012
missense_variant
rs1801133
c.665C>T;c.788C>T;c.734C>T;c.419C>T
p.Ala222Val
Meta-analysis of 23 case-control studies
Meta-analysis