Patients with cobalamin G or J defect missed by the current newborn screening program: diagnosis and novel mutations

Cobalamin G (cblG) and cobalamin J (cblJ) defects are rare disorders of cbl metabolism caused by MTR and ABCD4 mutations, respectively. Patients with atypical biochemical features can be missed by current newborn screening using tandem mass spectrometry (MS/MS), in which total homocysteine (tHCY) in dried blood spots (DBS) is not a primary biomarker. Two Chinese patients suspected of cbl defect but missed by newborn screening were studied. Using comprehensive metabolic analyses including MS/MS assay for tHCY in DBS, slightly low methionine in Patient 1, methymalonic aciduria in Patient 2, and homocysteinemia in both patients were detected, and DBS tHCY of two patients were obviously elevated (59.22 μmol/L, 17.75 μmol/L) compared to 140 healthy controls (2.5th-97.5th percentile, 1.05-8.22 μmol/L). Utilizing whole-exome sequencing, we found two novel MTR variants c.871C>T (p.Pro291Ser) and c.1771C>T (p.Arg591*) in Patient 1, and a ABCD4 homozygous variant c.423C>G (p.Asn141Lys) in Patient 2. Our study identified the first cblG patient and cblJ patient in mainland China, and highlighted comprehensive metabolic analyses and genetic tests in patients suspected of cbl defects. It also indicated that supplementary MS/MS assay for tHCY in DBS may be practical for early diagnosis of homocysteinemia, without repeated blood sampling.