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Severe microcephaly

Gene: SLC1A4

Amber List (moderate evidence)

SLC1A4 (solute carrier family 1 member 4)
EnsemblGeneIds (GRCh38): ENSG00000115902
EnsemblGeneIds (GRCh37): ENSG00000115902
OMIM: 600229, Gene2Phenotype
SLC1A4 is in 8 panels

2 reviews

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Following confirmation from the Genomics England clinical team that progressive microcephaly (to the severe range) is within scope of this panel, recommending a green rating for this gene at the next review.
Created: 8 Jun 2021, 3:38 p.m. | Last Modified: 8 Jun 2021, 3:38 p.m.
Panel Version: 2.206
Comment on list classification: Promoting this gene from grey to amber but with a recommendation for Green review, following confirmation that progressive microcephaly is within the scope of this panel. 4 different variants reported.
Created: 26 May 2021, 3:55 p.m. | Last Modified: 26 May 2021, 3:55 p.m.
Panel Version: 2.185
Associated with Spastic tetraplegia, thin corpus callosum, and progressive microcephaly #616657 (AR) in OMIM.

16 individuals reported with 4 different variants. 4 have progressive microcephaly reaching a head circumference <0.4th centile/beyond -3SD. One of the variants is a founder variant, E256K, found in the Ashkenazi Jewish population at a frequency estimated to be 0.7%.

PMID: 25930971 - Srour et al 2015 - analysed 2 affected siblings with severe intellectual disability, microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. They identified a homozygous missense variant in SLC1A4 (c. 766G>A [p. E256K]) in the two siblings. It was not found to be homozygous in any of the 11 unaffected siblings or their parents. The first sibling was normocephalic at birth, and no microcephaly was noted in the other. By ages of 7 and 2.5 years both had head circumferences below the second percentile as well as global developmental delay.

PMID: 26138499 - Heimer et al 2015 - report 2 unrelated patients (one Ashkenazi Jewish decent, the other of Ashkenazi-Iraqi Jewish decent), with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum. WES revealed that the Ashkenazi patient is homozygous for the same missense c.766G>A, p.(E256K) variant as reported by Srour et al. The Ashkenazi-Iraqi patient is compound heterozygous for this variant and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Progressive microcephaly was noted in both patients (Ashkenazi-Iraqi patient head circumference 25th percentile at birth, −3 SD at 1 year and −4 SD at 2.5  years; Ashekenazi patient 50th percentile at birth, −2 SD at 1.5 year, −3 SD at 3 years and −4 SD at 5 years).

PMID: 26041762 - Damseh et al 2015 - 10 Ashkenazi-Jewish patients from 8 families with microcephaly and significant developmental delay, plus a patient with consanguineous parents of Palestinian origin. 3 patients had a head circumference <3rd centile at birth, and 10/11 had head circumference <3rd centile at the current time (ages 3 -15 yo). However, no more precise centile information given, so cannot be sure if they come in the severe microcephaly category. 9 patients had the previously reported c.766G>A; p.E256K variant and a shared haplotype. Patient 10 was compound heterozygous for p.E256K and c.944_945del, p.L315fs, while the Palestinian patient had different homozygous variant in SLC1A4:c.1369C>T:p.R457W which segregated with the disease in the family. The carrier frequency for the SLC1A4 p.E256K variant in the AJ population was found to be 0.7%,

PMID: 27193218 - Conroy et al 2016 - report an Irish proband with neurodevelopmental delay, microcephaly and then seizures from 5 mo. Head circumference was 0.4th centile at birth and progressed to below 0.4th centile by 5 mo. A novel homozygous variant in SLC1A4;c.1358G>Alp.Trp453* was detected which was heterozygous in each of the parents.

PMID: 29989513 - Pironti et al 2018 - report a 7 yo Italian boy who presented with epileptic encephalopathy, congenital microcephaly, global developmental delay, severe hypotonia, spasticity predominant at the lower limbs, and thin corpus callosum. Using WES they identified a novel homozygous variant in SLC1A4 that they propose to be disease causing (c.1141G > A: p.Gly381Arg). Head circumference was 3rd centile at birth, but was <0.4th centile by age 7.
Created: 26 May 2021, 3:52 p.m. | Last Modified: 26 May 2021, 3:52 p.m.
Panel Version: 2.184

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic tetraplegia, thin corpus callosum, and progressive microcephaly OMIM:616657

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Spastic tetraplegia, thin corpus callosum, and progressive microcephaly is an autosomal recessive neurodevelopmental disorder characterized by onset of those features and severely impaired global development in early infancy. Most patients are unable to achieve independent walking or speech; some patients have seizures. Multiple affected families reported. Note founder variant p.Glu256Lys is a common founder variant in the Ashkenazi Jewish population.
Sources: Expert list
Created: 3 Sep 2020, 8:10 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, OMIM:616657
Tags
founder-effect Q2_21_rating
OMIM
600229
Clinvar variants
Variants in SLC1A4
Penetrance
None
Publications
Panels with this gene

History Filter Activity

8 Jun 2021, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: slc1a4 has been classified as Amber List (Moderate Evidence).

27 May 2021, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, OMIM:616657

26 May 2021, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: slc1a4 has been classified as Amber List (Moderate Evidence).

26 May 2021, Gel status: 0

Added Tag, Added Tag

Eleanor Williams (Genomics England Curator)

Tag founder-effect tag was added to gene: SLC1A4. Tag Q2_21_rating tag was added to gene: SLC1A4.

3 Sep 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Zornitza Stark (Australian Genomics)

gene: SLC1A4 was added gene: SLC1A4 was added to Severe microcephaly. Sources: Expert list Mode of inheritance for gene: SLC1A4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC1A4 were set to 25930971; 26138499; 26041762; 27193218; 29989513 Phenotypes for gene: SLC1A4 were set to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657 Review for gene: SLC1A4 was set to GREEN