Mutations inSLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination

Abstract

The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

Clinical application of whole-exome sequencing across clinical indications

“…Utilizing the power of our large data set, we were able to identify novel candidate genes in which multiple patients with similar phenotypes had rare variants predicted to result in loss of function, many of which were de novo. Access to this large number of cases has proven extremely valu- [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] As a result of our experience, we believe that candidate genes should be reported from WES analysis and shared in databases, such as GeneMatcher, so that clinicians, researchers, and clinical laboratories can be connected to facilitate more rapid dissemination of information and validation of novel disease genes. Our series is larger than previously reported clinical diagnostic series and has the power to begin to address the yield of WES for a large number of clinical indications.…”

Serine biosynthesis and transport defects

“…It has been suggested that other transporters are responsible for the extrusion of serine from the astroglial cells into the CSF; therefore, CSF serine level remains normal despite the defective ASCT1 transporter [3]. All previously reported children with serine transport defect were diagnosed through whole exome sequencing which identified biallelic mutations in the SLC1A4 gene encoding the ASCT1.…”

“…Serine transport defect resulting from deficiency of the ASCT1, the main transporter for serine in the central nervous system, has been recently described in children with neurological manifestations that overlap with those observed in serine biosynthesis defects (Table 1) [4,3,5].…”

“…Common brain abnormalities in neuroimaging include thin corpus callosum, hypomyelination, and brain atrophy. Less frequent manifestations include irritability, hyperactivity, sleep disorder, stereotypies, and strabismus [4,3,5].…”

“…Mature neurons are unable to biosynthesize serine, and are thus dependent on serine uptake. Defects in serine transport have been recently described to result in phenotypes that overlap with serine biosynthesis defects [3][4][5]. In this review article, we discuss serine biosynthesis and its utilization, function, and neuronal transport.…”