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March 14, 2026Open Access

Association of Common Methylenetetrahydrofolate Reductase Polymorphisms with Congenital Cardiac Defect and Hypothyroidism in Down Syndrome Children

Key Points

Investigate the association of MTHFR polymorphisms with congenital cardiac defects and hypothyroidism in down syndrome.
Enrolled 75 children with down syndrome and 30 matched controls.
Quantified homocysteine and cysteine using LC-MS.
Sequenced MTHFR polymorphisms via Sanger method.
Higher cysteine levels found in children with down syndrome.
MTHFR variants 677T and 1298C overrepresented among down syndrome children compared to controls.
Children with cardiovascular and thyroid comorbidities had significantly higher homocysteine and cysteine levels.

Abstract

Objectives: Down Syndrome (DS) is a common aneuploidy involving chromosome 21, wherein abnormalities in folate pathway are documented in several studies. Dysregulation of methylene tetra hydro folate reductase (MTHFR) activity leads to altered homocysteine levels, which is a risk factor for vascular diseases. The two functionally relevant polymorphisms C677T and A1298C in MTHFR gene are associated with various thromboembolic events. The comorbidities in DS include congenital cardiac defects (CCD), thyroid disorders and subnormal intellect. However, the correlation between these comorbidities in DS with several parameters viz. homocysteine or cysteine levels as well as MTHFR polymorphisms are not fully explored. Therefore, the present study is an attempt to investigate these parameters in DS children. Material and Methods: Seventy-five individuals with DS and thirty age and sex matched healthy control children were enrolled with informed consent for this study. The homocysteine and cysteine levels were quantitated using LC-MS while Sanger method was used for sequencing of MTHFR polymorphisms. Results: Significantly higher levels of cysteine were observed in DS children. Analysis of the two MTHFR variants revealed over representation of 677T and 1298C in children with DS compared to the healthy controls. On stratified analysis it was observed that DS children with comorbidities (hypothyroidism and/or congenital heart defect) had overrepresentation of MTHFR 677T and 1298C along with significantly higher levels of homocysteine and cysteine as compared to patients without comorbidities. Conclusion: Our findings suggest that MTHFR variants (677T, 1298C) along with elevated homocysteine and cysteine levels may serve as potential biomarkers for hypothyroidism in Down syndrome. Our results could be predictive for DS associated comorbidities with scope for better prognostication and counselling in these patients.

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