Mutation Analysis
The 24 families carry 27 distinct SLC25A38 mutations (Table 2). Sixteen (16) of these mutations have been described by us and others previously. Eleven (11) mutations are novel, including one MS allele (c.388G>A; p.Gly130Arg), 5 frameshift (FS) alleles (c.207_214del, p.Met70Cysfs*80; c.362del, p.Pro121Glnfs*26; c.475del, p.Glu159Argfs*7; c.669_682del, p.Cys223Trpfs*67; and c.809dup, p.Phe271Leufs*24), and 5 variants predicted to interrupt splicing (c.70-2A>C, c.276+1G>A, c.277-2A>C, c.457-1G>T, and c.792+5G>C). In contrast to many of the previously reported pathogenic alleles, which are generally more common (see below), only one of these variants occurs in a sequence with a predisposition to mutation: the c.207_214del involves a deletion of a 7 base-pair direct repeat. Furthermore, only two of the novel mutations, c.457-1G>T (rs1448237170, MAF 4.00x10-6) and c.669_682del (rs781372292, MAF 1.77x10-5), are recorded in references databases such as gnomAD (gnomad.broadinstitute.org).
As expected in a rare recessive disease, 19 of the 24 families (79%) are homozygous for the pathogenic mutation. In the patients with homozygous mutations, 10 are known to be consanguineous and 5 are from geographically or ethnically restricted populations that may be genetically less diverse.
In this cohort, we detected no difference in age of onset of anemia, age at initial transfusion, pre-transfusion HGB, or transfusion interval among patients with two null alleles, two splicing alleles, or at least one MS mutation (data not shown).