Hereditary Folate Malabsorption via the SLC46A1 Gene

Hereditary Folate Malabsorption (HFM) is a hereditary folate deficiency disorder that is characterized by defective intestinal folate absorption and impaired folate transport into the central nervous system. This results in low concentrations of folate in the serum and cerebrospinal fluid (Diop-Bove et al. 2014). In addition, some patients may be found to excrete formiminoglutamic acid (FIGLU) and/or orotic acid in the urine (Watkins and Rosenblatt 2014). Clinically, HFM is characterized by poor feeding and failure to thrive, severe megaloblastic anemia that may be accompanied by thrombocytopenia and/or leukopenia, diarrhea, mouth ulcers, hypoimmunoglobulinemia and other immunological dysfunction which may lead to infection with unusual organisms. The immunological deficiency may be severe enough to mimic severe combined immune deficiency (SCID), and undiagnosed infants may die early due to recurrent infections. Untreated patients that survive into early childhood may present with progressive neurological symptoms such as developmental delay, cognitive and motor impairment, seizures, ataxia and behavioral disorders (Diop-Bove et al. 2014; Watkins and Rosenblatt 2014). The onset of symptoms is usually at a few months of age as folate stores accumulated during gestation become depleted (Diop-Bove et al. 2014).

Early and correct diagnosis of HFM patients is essential for proper treatment. If treatment is initiated early in life, the signs and symptoms of the disorder may be prevented or reversed. If treatment is delayed, neurological defects may become permanent, and HFM may be fatal in untreated individuals (Zhao et al. 2007; Diop-Bove et al. 2014). Treatment generally consists of parenteral or high-dose oral administration of folinic acid, and is life-long for affected individuals (Diop-Bove et al. 2014).

Hereditary Folate Malabsorption is an autosomal recessive disorder, and the SLC46A1 gene is the only gene known to be associated with HFM (Qiu et al. 2006; Diop-Bove et al. 2014; Watkins and Rosenblatt 2014). This gene encodes the proton-coupled folate transporter protein, which is responsible for folate uptake in the intestines and across the blood-brain barrier (Diop-Bove et al. 2014). HFM is a rare disorder, with fewer than 20 pathogenic variants reported in the literature. Approximately half of the reported variants are missense. The remaining variants are mix of nonsense and splicing variants, as well as small deletions and insertions (Human Gene Mutation Database). The only common pathogenic variant reported thus far is a splice variant (c.1082-1G>A) which is common in individuals of Puerto Rican descent (Qiu et al. 2006; Mahadeo et al. 2011; Diop-Bove et al. 2014).

At this time, the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature. However, analytical sensitivity of this test is expected to be high as, to date, all identified patients have been found to have two pathogenic variants detectable via direct sequencing (Zhao et al. 2007; Mahadeo et al. 2011; Shin et al. 2011; Diop-Bove et al. 2014).

This test provides full coverage of all coding exons of the SLC46A1 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).