A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly

Clin Genet. 2015 Jul;88(1):e1-4. doi: 10.1111/cge.12605. Epub 2015 May 28.


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.

Keywords: Ashkenazi Jewish; SLC1A4; exome sequencing; intellectual disability; microcephaly; neutral amino acid.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Transport System ASC / genetics*
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Exons
  • Female
  • Gene Frequency
  • Humans
  • Infant
  • Infant, Newborn
  • Intellectual Disability / genetics*
  • Jews / genetics
  • Male
  • Microcephaly / genetics*
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Siblings


  • Amino Acid Transport System ASC
  • SLC1A4 protein, human