We performed exome analysis in two affected siblings with
severe intellectual disability (ID), microcephaly and spasticity
from an Ashkenazi Jewish consanguineous family.
We identified only one rare variant, a missense in SLC1A4
(c. 766G>A [p. E256K]), that is homozygous in both siblings
but not in any of their 11 unaffected siblings or their
parents (Logarithm of odds, LOD score: 2.6). This variant
is predicted damaging. We genotyped 450 controls of
Ashkenazi Jewish ancestry and identified only 5 individuals
who are heterozygous for this variant (minor allele
frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter
for neutral aminoacids such as alanine, serine, cysteine
and threonine. l-Serine is essential for neuronal survival
and differentiation. Indeed, l-serine biosynthesis disorders
affect brain development and cause severe ID. In the brain,
l-serine is synthesized in astrocytes but not in neurons.
It has been proposed that ASCT1 mediates the uptake of
l-serine into neurons and the release of glia-borne l-serine
to neighboring cells. SLC1A4 disruption may thus impair
brain development and function by decreasing the levels of
l-serine in neurons. The identification of additional families
with mutations in SLC1A4 would be necessary to confirm its
involvement in ID.