Journal
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Volume 188, Issue 4, Pages 1124-1141Publisher
WILEY
DOI: 10.1002/ajmg.a.62627
Keywords
C3-acylcarnitine; CD320; cobalamin; newborn screening; transcobalamin receptor; transcobalamin receptor deficiency
Categories
Funding
- Canadian Institutes for Health Research [148661]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-DK-7-3431]
- Hess B.and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone
- National Human Genome Research Institute Intramural Research Program
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The p.E88del variant in the transcobalamin receptor, CD320, shows functional consequences and clinical significance in cell culture and genetic association studies, with homozygous newborns at low risk of requiring clinical intervention and minimal effects on cobalamin metabolism.
The biological and clinical significance of the p.E88del variant in the transcobalamin receptor, CD320, is unknown. This allele is annotated in ClinVar as likely benign, pathogenic, and of uncertain significance. To determine functional consequence and clinical relevance of this allele, we employed cell culture and genetic association studies. Fibroblasts from 16 CD320 p.E88del homozygotes exhibited reduced binding and uptake of cobalamin. Complete ascertainment of newborns with transiently elevated C3 (propionylcarnitine) in New York State demonstrated that homozygosity for CD320 p.E88del was over-represented (7/348, p < 6 x 10(-5)). Using population data, we estimate that similar to 85% of the p.E88del homozygotes born in the same period did not have elevated C3, suggesting that cobalamin metabolism in the majority of these infants with this genotype is unaffected. Clinical follow-up of 4/9 homozygous individuals uncovered neuropsychological findings, mostly in speech and language development. None of these nine individuals exhibited perturbation of cobalamin metabolism beyond the newborn stage even during periods of acute illness. Newborns homozygous for this allele in the absence of other factors are at low risk of requiring clinical intervention, although more studies are required to clarify the natural history of various CD320 variants across patient populations.
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