Transcobalamin II Deficiency via the TCN2 Gene

Transcobalamin II is an inherited disorder that results from defective transport of cobalamin (vitamin B12) into tissues and cells (Li et al. 1994a; Carrillo et al. 2013; Ünal et al. 2015). Onset is in early infancy, and is characterized by gastrointestinal symptoms such as vomiting and diarrhea, hematological deficiencies (including megaloblastic anemia and pancytopenia), failure to thrive, and eventual neurological complications in some patients, especially if treatment is delayed. Neurological complications can include developmental delay, seizures and cerebellar disturbances. Retinopathy due to macular degeneration has also been reported (Li et al. 1994a; Häberle et al. 2009; Schiff et al. 2010; Carrillo et al. 2013; Ünal et al. 2015). Metabolic test results reveal that these patients have normal serum cobalamin levels, but low serum transcobalamin. Most also are found to have methylmalonic aciduria and homocystinuria (Schiff et al. 2010; Carrillo et al. 2013; Ünal et al. 2015).

Treatment, usually with intramuscular injections of hydroxocobalamin, can help with hematological and biochemical disburbances, but may not completely prevent neurological complications (Namour et al. 2003; Schiff et al. 2010; Ünal et al. 2015). Earlier treatment seems to result in a better outcome for these patients (Schiff et al. 2010).

Transcobalamin II deficiency is an autosomal recessive disorder caused by defects in the TCN2 gene, which is located at chromosome 22q12.2. Over 25 pathogenic variants have been reported in the TCN2 gene, nearly all of which have been nonsense, splicing, or protein truncating variants, or larger copy number variants (Human Gene Mutation Database). One single amino acid deletion has been reported (His167del); this amino acid resides in the transcobalamin receptor binding region (Schiff et al. 2010). Thus far, no missense variants have been associated with transcobalamin II deficiency. Most reported TCN2 variants seem to be private, familial variants.

The transcobalamin II (TC II) protein is responsible for the transport of cobalamin from the blood into the cells via receptor-mediated endocytosis. Cobalamin-associated TC II enters the lysosomes where the TC II protein is degraded, freeing the cobalamin moiety for downstream reactions (Li et al. 1994a; Häberle et al. 2009).

Based on collective totals of transcobalamin II deficient patients reported in the literature, the clinical sensitivity of TCN2 sequencing is estimated to be ~73% (29 pathogenic TCN2 alleles out of 40 total alleles, with only one patient counted if multiple family members were affected) (Li et al. 1994a; Li et al. 1994b; Namour et al. 2003; Prasad et al. 2008; Häberle et al. 2009; Ratschmann et al. 2009; Nissen et al. 2010; Schiff et al. 2010; Ünal et al. 2015; Pupavac et al. 2016). The remaining ~27% of alleles contained exonic or larger deletions that may not be detected by sequencing.

This test provides full coverage of all coding exons of the TCN2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).