Unmasking Genetic Mechanisms for Homocystinuria due to Methylenetetrahydrofolate Reductase Deficiency

Abstract We report a female infant presenting with neonatal encephalopathy, seizures, and hyperhomocysteinemia. Genetic investigations revealed a homozygous variant, NM_005957.4 (methylenetetrahydrofolate reductase [MTHFR]): c.1031G>T; p. (Arg344Met). Unexpectedly, parental genetic testing showed maternal carrier status for MTHFR with paternal absence of the variant. Further genomic analysis, including autozygosity mapping confirmed maternal uniparental disomy (UPD) of chromosome 1 as the underlying genetic mechanism. The case underscores the importance of considering UPD in the diagnostic evaluation of autosomal recessive disorders, especially when parental carrier status does not align with expected inheritance patterns. Comprehensive genetic analysis, including segregation studies and advanced mapping tools, is crucial for accurate diagnosis, enabling targeted treatment and informed genetic counseling.