Abstract / Summary
Purpose Classical homocystinuria due to cystathionine beta-synthase (CBS) deficiency is a rare autosomal recessive disorder of sulfur amino acid metabolism. Uniparental isodisomy has not been previously reported as a pathogenetic mechanism for this disorder. We report a case of CBS deficiency resulting from maternal segmental uniparental isodisomy. Methods A female child presenting with ectopia lentis, developmental delay, and autism spectrum disorder underwent biochemical testing and trio clinical exome sequencing at 63 months of age. Bioinformatic analysis included a one-carbon metabolism gene panel and phenotype-driven variant prioritization using Human Phenotype Ontology terms. Regions of homozygosity were identified from exome data, and uniparental disomy was confirmed by microsatellite analysis using short tandem repeat markers spanning chromosome 21. Results Markedly elevated plasma homocysteine (314 μmol/L) prompted genetic testing, which identified a homozygous pathogenic CBS (HGNC:1550) variant, NM_000071.3:c.451G>A (p.Gly151Arg). Segregation analysis revealed maternal heterozygosity and paternal absence of the variant, with maternal segmental uniparental isodisomy confirmed at the CBS locus. Initial treatment with pyridoxine and folic acid confirmed a pyridoxine-non-responsive phenotype, with only a modest decrease in plasma total homocysteine. Dietary management and vitamin B12 supplementation were added but limited by poor adherence. Following introduction of betaine therapy combined with improved adherence to nutritional management, plasma homocysteine decreased to 26 μmol/L within 8 months. Conclusion This case illustrates how segmental uniparental isodisomy can unmask autosomal recessive disease in offspring of non-consanguineous parents. The findings highlight the diagnostic value of regions of homozygosity analysis in trio exome sequencing and demonstrate effective biochemical control with combined pharmacological and nutritional management.