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).