Genes · 2026
Identification of CD320-Associated Cobalamin Transport Deficiency Through Newborn Screening Caused by Novel Homozygous Candidate Variants.
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Almalki Faisal, Alsofyany Amal Saleh, Almalki Abdulaziz K, Abu Shuaylan Ashraf Oudah, Alruqi Haya, Althobiti Jwaher Mesleh
Аннотация
BACKGROUND: The transcobalamin receptor, encoded by the CD320 gene, mediates the cellular uptake of the transcobalamin-cobalamin complex (vitamin B12). Pathogenic variants in CD320 impair the intracellular transport, resulting in methylmalonic acid (MMA) and propionylcarnitine (C3) level, despite normal circulating vitamin B12 levels, with variable clinical phenotypes.
METHODS: Whole-exome sequencing (WES) was carried out for a newborn screening positive proband. Further plasma metabolic investigation and blood gas analysis were carried out for the proband. Sanger sequencing was carried out to confirm the candidate variant and identify the familial segregation.
RESULTS: The proband presented with elevated C3 and MMA levels and exhibited an expanded clinical phenotype that included severe microcephaly, metabolic acidosis, low bicarbonate and pancytopenia. WES identified a homozygous missense candidate variant in the last amino acid of exon 1 in the CD320 gene (NM_016579.3: c.142G>C, p.Gly48Arg). Another adjacent synonymous homozygous candidate variant was identified (NM_016579.3: c.141A>C, p.Ala47=). Both variants were identified in a male proband from a consanguineous family. Both variants were confirmed by Sanger and segregated within the family members. During one year of follow-up, the patient showed persistent microcephaly while receiving a specialized metabolic formula and levocarnitine supplementation.
CONCLUSIONS: This study identified a novel recessive missense candidate variant and an adjacent synonymous candidate variant in CD320, supported with biochemical and clinical features of CD320-associated cobalamin transport deficiency. This suggests microcephaly may be a previously unrecognized phenotype with possible association of impaired intracellular cobalamin transport, while elevated C3 detected through routine newborn screening may be the earliest biochemical indicator of CD320-associated cobalamin transport deficiency.
METHODS: Whole-exome sequencing (WES) was carried out for a newborn screening positive proband. Further plasma metabolic investigation and blood gas analysis were carried out for the proband. Sanger sequencing was carried out to confirm the candidate variant and identify the familial segregation.
RESULTS: The proband presented with elevated C3 and MMA levels and exhibited an expanded clinical phenotype that included severe microcephaly, metabolic acidosis, low bicarbonate and pancytopenia. WES identified a homozygous missense candidate variant in the last amino acid of exon 1 in the CD320 gene (NM_016579.3: c.142G>C, p.Gly48Arg). Another adjacent synonymous homozygous candidate variant was identified (NM_016579.3: c.141A>C, p.Ala47=). Both variants were identified in a male proband from a consanguineous family. Both variants were confirmed by Sanger and segregated within the family members. During one year of follow-up, the patient showed persistent microcephaly while receiving a specialized metabolic formula and levocarnitine supplementation.
CONCLUSIONS: This study identified a novel recessive missense candidate variant and an adjacent synonymous candidate variant in CD320, supported with biochemical and clinical features of CD320-associated cobalamin transport deficiency. This suggests microcephaly may be a previously unrecognized phenotype with possible association of impaired intracellular cobalamin transport, while elevated C3 detected through routine newborn screening may be the earliest biochemical indicator of CD320-associated cobalamin transport deficiency.