A Rare Combination of Hereditary Folate Malabsorption (SLC46A1 Gene Variant) and Beta-Thalassemia Trait

Hereditary folate malabsorption is an autosomal recessive disorder caused by a pathogenic variant in SLC46A1, affecting proton-coupled folate transporter (PCFT) function. Infants with hereditary folate malabsorption often develop megaloblastic anemia and, without treatment, may experience serious neurodegenerative complications. Thalassemia is also an autosomal recessive genetic disorder. Major or compound heterozygous thalassemia is associated with severe complications and may require regular blood transfusions.

A couple is seeking guidance on the recurrence risk of the condition that led to the loss of their two previous children. The second child's medical history and laboratory findings indicate a low vitamin B12 level 137.5 pg/mL, "reference range 211-911 pg/mL", elevated homocysteine 34.98 μmol/L, "reference range 3.7-13.9 μmol/L", and ferritin levels at 1129 ng/mL "reference range 18.2-341.2 ng/mL". Hematological results show a hemoglobin level of 6.4 g/dL, a total reticulocyte count of 3.39%, MCV of 82.7 fL, MCH of 26.9 pg, RDW of 19.0%, neutrophils at 27%, and lymphocytes at 42%. Hb-HPLC analysis revealed an HbA2 level of 4.6%. Whole-exome sequencing identified a homozygous pathogenic variant in the SLC46A1 gene (c.1127G>A), associated with hereditary folate malabsorption and a heterozygous pathogenic variant in the HBB gene (c.92+5G>C), linked to β-thalassemia. The first child's medical history also suggests low vitamin B12 levels and elevated homocysteine and ferritin levels. Hb-HPLC showed normal results, and genetic testing was not undertaken.

The homozygous SLC46A1 (c.1127G>A) variant is lethal, whereas a heterozygous state with SLC46A1 (c.1127G>A) and HBB (c.92+5G>C) may not be associated with complications like transfusion-dependent thalassemia.