High penetrance and phenotypic landscape of methylenetetrahydrofolate reductase c.665 C>T polymorphism in the absence of folate fortification.
PMID 39608496 | DOI 10.1016/j.clnesp.2024.11.027 · Clinical nutrition ESPEN · 2025 · View on PubMed ↗
BACKGROUND: Studies have linked the methylenetetrahydrofolate reductase (MTHFR) c.665C > T (rs1801133) with hyperhomocysteinemia. Mandatory folate fortification nullified this association. However, its relevance persists in regions with no folate fortification resulting in a relatively low frequency of this variant in healthy population. This study explored the MTHFR variant's association with 50 clinical manifestations in the absence of folate fortification. METHODS: We performed mutation analysis via whole exome and Sanger sequencing in 2431 cases and 1265 healthy controls and the food frequency-based dietary folate intake assessment. RESULTS: The cohort's average dietary folate intake was 373 ± 141 μg/day. MTHFR rs1801133 variant demonstrated ≥4.49-fold increased risk for respiratory distress, recurrent pregnancy loss (RPL), ischemic stroke, autism, global developmental delay, dysplasia, myoclonic jerks, intellectual disability, aggressive behavior, motor delay, Alzheimer's, cerebellar atrophy, failure to thrive, cerebral atrophy, increased tendon reflexes, and spasticity (p < 0.0001). MTHFR T-allele showed 1.81-4.04 folds increased risk for mental retardation, behavioral problems, dystonia, anemia, gait abnormality, hypotonia, recurrent pneumonia, liver disease, cerebral palsy, short stature, hyperactivity, and cognitive decline. The association of this variant with seizures was moderate (OR: 1.51, 95 % CI: 1.13-2.02, p = 0.009). MTHFR TT-genotype was associated with a 5.81-fold risk for the abnormal phenotype (95 % CI: 1.39-24.28, p = 0.005). MTHFR T-allele was associated with low 25-hydroxy vitamin D, Ferritin, TIBC, and elevated total cholesterol. CONCLUSION: The MTHFR rs1801133 increases the risk for RPL, developmental milestones, neuronal development, autism, ischemic stroke, and late-onset neurological functions. The MTHFR TT-genotype is strongly associated with abnormal phenotypes.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | MTHFR | “BACKGROUND: Studies have linked the methylenetetrahydrofolate reductase (MTHFR) c.665C > T (rs1801133) with hyperhomocysteinemia.” | 0.98 | hgnc_dict_v1 |
| phenotype | intellectual disability | “MTHFR rs1801133 variant demonstrated ≥4.49-fold increased risk for respiratory distress, recurrent pregnancy loss (RPL), ischemic stroke, autism, global developmental delay, dysplasia, myoclonic jerks, intellectual disability, aggressive behavior, motor delay, Alzheimer's, cerebellar atrophy, failure to thrive, cerebral atrophy, increased tendon reflexes, and spasticity (p < 0.0001).” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | developmental delay | “MTHFR rs1801133 variant demonstrated ≥4.49-fold increased risk for respiratory distress, recurrent pregnancy loss (RPL), ischemic stroke, autism, global developmental delay, dysplasia, myoclonic jerks, intellectual disability, aggressive behavior, motor delay, Alzheimer's, cerebellar atrophy, failure to thrive, cerebral atrophy, increased tendon reflexes, and spasticity (p < 0.0001).” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | stroke | “MTHFR rs1801133 variant demonstrated ≥4.49-fold increased risk for respiratory distress, recurrent pregnancy loss (RPL), ischemic stroke, autism, global developmental delay, dysplasia, myoclonic jerks, intellectual disability, aggressive behavior, motor delay, Alzheimer's, cerebellar atrophy, failure to thrive, cerebral atrophy, increased tendon reflexes, and spasticity (p < 0.0001).” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | recurrent pregnancy loss | “MTHFR rs1801133 variant demonstrated ≥4.49-fold increased risk for respiratory distress, recurrent pregnancy loss (RPL), ischemic stroke, autism, global developmental delay, dysplasia, myoclonic jerks, intellectual disability, aggressive behavior, motor delay, Alzheimer's, cerebellar atrophy, failure to thrive, cerebral atrophy, increased tendon reflexes, and spasticity (p < 0.0001).” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | autism spectrum disorder | “MTHFR rs1801133 variant demonstrated ≥4.49-fold increased risk for respiratory distress, recurrent pregnancy loss (RPL), ischemic stroke, autism, global developmental delay, dysplasia, myoclonic jerks, intellectual disability, aggressive behavior, motor delay, Alzheimer's, cerebellar atrophy, failure to thrive, cerebral atrophy, increased tendon reflexes, and spasticity (p < 0.0001).” | 0.93 | phenotype_alias_lexicon_v2 |
| phenotype | epilepsy | “The association of this variant with seizures was moderate (OR: 1.51, 95 % CI: 1.13-2.02, p = 0.009).” | 0.93 | phenotype_alias_lexicon_v2 |
| variant | rs1801133 | “BACKGROUND: Studies have linked the methylenetetrahydrofolate reductase (MTHFR) c.665C > T (rs1801133) with hyperhomocysteinemia.” | 0.90 | hgvs_regex_v1 |