The SLC25A38 mutation spectrum
Currently, there are 16 publications, including the current one, describing, a total of 92 SLC25A38 CSA families from diverse geographic and ethnic backgrounds (Table 5). As is true of our sample, approximately three-quarters (77%) of the reported probands carry homozygous mutant alleles (Figure 1A). In one case, homozygosity is the result of constitutional uniparental isodisomy (Andolfo et al., 2020). MS (36%), frameshift (27%) and stop-gained (27%) alleles each constitute one-quarter to one-third of alleles detected in probands (Figure 1B). Variants predicted to affect splicing (9%) or cause a stop-loss (EXT, 1%) are comparatively rare. Two MS variants, c.560G>C; p.Arg187Pro and c.625G>C; p.Asp209His, are also predicted to affect splicing, the former likely activating a cryptic splice acceptor site within exon 5 and the latter altering the conserved G at the last base pair of exon 5. Patients homozygous for MS mutations are most common, constituting approximately one-third (31%) of all reported probands (Figure 1C). Whereas 42% of patients bear at least one MS allele and may retain some transport function, 46% have two stop-gained or frameshift (or a combination of both) presumptive null alleles, and another 12% have two splicing alleles or a splicing allele in trans of a frameshift or stop-loss allele, also likely to retain little transport activity (Figure 1D).
Of the 47 reported disease-associated mutations, 12 occur at sequences prone to recurrence, including 9 at CpG dinucleotides and 3 at a direct or simple repeat. Of the 21 apparently recurrent mutations, 9 are at a CpG or repeat (Figure 2).
Pathogenic MS mutations are distributed nearly exclusively in the transmembrane (TM) domains. Of the 21 pathogenic MS mutations, 19 are located in amino acids within a TM domain (Table 5 and Figure 2). One of the remaining two, c.625G>C; p.Asp209His, is also predicted to affect splicing. The remaining variant, c.469G>C; p.Gly157Arg, in addition to be located between TM3 and TM4, is conserved neither in SLC25 family members, nor in SLC25A38 orthologues. There is no difference in the relative conservation of amino acids in TM and non-TM regions of SLC25A38 orthologues (Mann-Whitney P=0.385) whereas there is an unexpected predominance of disease-causing mutations present in TMs (χ2 P<0.001). Of the TM residues with pathogenic mutations, there is a trend toward being relatively conserved compared to other TM amino acids (Mann-Whitney P=0.085)