Novel compound heterozygous mutations of MTHFR Gene in a Chinese family with homocystinuria due to MTHFR deficiency

Abstract Background Homocystinuria due to methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. The purpose of this study is to expand the mutation site of the MTHFR gene and provide genetic counseling for this family. Methods A couple came to our hospital for pre-pregnancy genetic counseling. We collected the family history and detailed clinical information, then performed whole-exome sequencing, and analyzed the pathogenicity of the candidate mutations. Results We found that the father of the proband had homocystinuria, the proband and his brother had low blood methionine levels at birth, and the brain MRI showed brain dysplasia. The third fetus was found to have a broadened triangle of the bilateral ventricle at 19 weeks of pregnancy. The compound heterozygous variants of c.602 A > C (p.His201Pro) and c.1316T > C (p.Leu439Pro) of the MTHFR gene in the first three fetuses were found by whole-exome sequencing. The heterozygous c.602 A > C variant of the MTHFR gene is a novel missense variant that has been submitted to the ClinVar with Variation ID 992,662. Conclusion In consideration of the clinical phenotype, family history, and result of genetic testing, we speculated that both patients may have homocystinuria due to MTHFR deficiency. Homocystinuria due to MTHFR deficiency caused by compound heterozygous mutations composed of the MTHFR gene in this family may be associated with cerebral atrophy and cerebral dysplasia. The novel compound heterozygous mutations broaden the mutation spectrum of the MTHFR gene and enhance the application of genetic counseling and carrier screening in rare diseases.