TY - JOUR
T1 - Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene
AU - Pangilinan, Faith
AU - Watkins, David
AU - Bernard, David
AU - Chen, Yue
AU - Dong, Ningzheng
AU - Wu, Qingyu
AU - Ozel-Abaan, Hatice
AU - Kaur, Manjit
AU - Caggana, Michele
AU - Morrissey, Mark
AU - Browne, Marilyn L.
AU - Mills, James L.
AU - Van Ryzin, Carol
AU - Shchelochkov, Oleg
AU - Sloan, Jennifer
AU - Venditti, Charles P.
AU - Sarafoglou, Kyriakie
AU - Rosenblatt, David S.
AU - Kay, Denise M.
AU - Brody, Lawrence C.
N1 - Publisher Copyright:
© 2022 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
PY - 2022/4
Y1 - 2022/4
N2 - 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 × 10−5). Using population data, we estimate that ~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.
AB - 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 × 10−5). Using population data, we estimate that ~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.
KW - C3-acylcarnitine
KW - CD320
KW - cobalamin
KW - newborn screening
KW - transcobalamin receptor
KW - transcobalamin receptor deficiency
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U2 - 10.1002/ajmg.a.62627
DO - 10.1002/ajmg.a.62627
M3 - Article
C2 - 35107211
AN - SCOPUS:85124355430
SN - 1552-4825
VL - 188
SP - 1124
EP - 1141
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 4
ER -