Concerning “Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes” by Farwell Gonzalez et al.

Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment

“…The more severe presentation in patient 1a could perhaps have been enhanced by impaired cobalamin export out of the lysosome due heterozygous loss of function of LMBRD1 . However, after disproving the conclusions of Farwell Gonzalez et al, 11 there is, as of yet, no evidence for a role of digenic inheritance in the cobalamin metabolism pathway 12 …”

“…However, after disproving the conclusions of Farwell Gonzalez et al, 11 there is, as of yet, no evidence for a role of digenic inheritance in the cobalamin metabolism pathway. 12 Along with genotype, unpredictable effects of in utero exposure, as well of the degree of biochemical control following diagnosis, also may factor into the differing clinical and neurologic outcomes described in cblG. We assume that better biochemical control results in improved outcomes.…”

“…11 Digenic inheritance leading to a deficiency in the cobalamin associated re-methylation pathway was postulated, 11 but later disproven. 12 The correct diagnosis of cblG was not made until the birth of Patient 1b.…”

“…Follow‐up whole exome sequencing on the parents revealed a maternal variant in MTR c.3518C >T, p.(Pro1173Leu) and a paternal variant in LMBRD1 c.1056delG; p.(L352Lfs*18) associated with cobalamin F disease ( cblF ) 11 . Digenic inheritance leading to a deficiency in the cobalamin associated re‐methylation pathway was postulated, 11 but later disproven 12 . The correct diagnosis of cblG was not made until the birth of Patient 1b.…”

“…Rapid whole genome sequencing identified biallelic mutations in MTR at 4 days of life: c.3518C>T p.(Pro1173Leu) and a 3.5 kb deletion encompassing exons 29 and 30. 12 On complementation analysis, methylTHF incorporation in patient fibroblasts was corrected toward reference levels after fusion with cblE fibroblasts (7.2 pmol/mg protein/18 hours without fusion; 21.4 pmol/mg protein/18 hours with fusion), while no complementation occurred when patient and cblG fibroblasts were fused (10.1 without fusion and 7.6 with fusion), confirming the diagnosis of cblG. 1,13 His Colorado newborn screen was within the reference range.…”