Two unrelated patients, presenting with significant global developmental
delay, severe progressive microcephaly, seizures, spasticity and thin corpus
callosum (CC) underwent trio whole-exome sequencing. No candidate
variant was found in any known genes related to the phenotype. However,
crossing the data of the patients illustrated that they both manifested
pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter
of serine and other neutral amino acids. The Ashkenazi patient is
homozygous for a deleterious missense c.766G>A, p.(E256K) mutation
whereas the Ashkenazi-Iraqi patient is compound heterozygous for this
mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation.
Structural prediction demonstrates truncation of significant portion of the
protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.