Early onset or syndromic epilepsy

Gene: SLC35A3

I don't know

AR AMRS. Edvardson et al 2013 (24031089) large kindred of AJ descent in which 8 individuals had arthrogryposis, MR, autism spectrum dosirder and epilepsy. 6/8 developed localisation-related or atypical absence seizures between 3 and 11 years of age. Compound het variants identified Q172* and 866A>G. Patient cells showed no normal transcript, indicating that they had no functional SLC35A3 protein. Marini et al, 2017 (28328131) non consang Italian family where 2 siblings (boy and girl) had severe EE with skeletal anomalies - compound het for a missense and a fs variant. Edmondson et al, 2017 (28777481) skeletal abnormalties and poor long term prognosis died at day 21. Had a novel hom missense variant. All the rest of the reported variants are compund het - possible hom more severe phenotype?

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Red List (low evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
epilepsy, arthrogryposis

Publications

• 28328131

I don't know

Kept rating as Amber based on Amber post-Webex review from Helen Lord.

Created: 9 Sep 2019, 10:41 a.m. | Last Modified: 9 Sep 2019, 10:41 a.m.

Panel Version: 1.320

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Added watchlist tag.

Created: 14 Feb 2019, 5:03 p.m.

Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Green by Konstantinos Varvagiannis. 1 case (multiple individuals from Ashkenazi Jewish kindred) in PMID:24031089 with epilepsy in many individuals. A second epilepsy case comes from PMID:28328131 (Marini et al. 2017). Epilepsy is not recorded in the SLC35A3‐related skeletal dysplasia patient from PMID:28777481 who died at 21days. ClinVar submissions weren't included as additional cases as individual phenotypes were not recorded. Therefore rated Amber awaiting further published or clinical cases.

Created: 14 Feb 2019, 5:03 p.m.

The 2013 (SCV000108589.2) and 2016 (SCV000699337.1) ClinVar submissions reported in the review by Konstantinos Varvagiannis link to the same publication: Edvardson et al. (2013, PMID:24031089).

Created: 14 Feb 2019, 5:01 p.m.

Marini et al. 2017 (PMID: 28328131) provide a second case. They report a non-consanguineous Italian family with two siblings manifesting severe EE. Both siblings exhibited infantile spasms associated with focal and tonic seizures from early infancy. In addition, both had quadriplegia, acquired microcephaly and severe ID. WGS identified novel compound het variants in SLC35A3 in both children.

Created: 14 Feb 2019, 4:57 p.m.

Edvardson et al. (2013, PMID:24031089) report 8 patients from a large kindred of Ashkenazi Jewish descent with Arthrogryposis, mental retardation, and seizures (MIM:615553) and a compound het variant: Gln-172-Ter plus c.886A>G splice site variant. Seizures were seen in 6 of 8 patients.

Created: 14 Feb 2019, 4:56 p.m.

Green List (high evidence)

Biallelic pathogenic variants in SLC35A3 cause Arthrogryposis, mental retardation, and seizures (MIM 615553).
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Edvardson et al. (PMID: 24031089) report on 8 affected individuals from 3 nuclear Ashkenazi Jewish families. All harbored a nonsense [NM_012243.1:c.514C>T / p.(Gln172*)] as well as a missense variant [NM_012243.1:c.886A>G / p.(Ser296Gly)] in the compound heterozygous state. Most of the parents, who were heterozygous for the one or the other variant, were distantly related.

Common features included ASD (8/8), arthrogryposis (8/8), seizures (6/8) and intellectual disability (6/8 - variable degrees).

Upon cDNA studies, the (predicted) missense variant led to skipping of exon 8 and there was no normal size transcript (as would be expected for a variant of this type). Introduction of a premature stop codon due to this variant as well instability of the mRNA from the Gln172Ter allele was presumed to lead to absence of functional SLC35A3 protein.

Testing of 2045 Ashkenazi Jewish individuals revealed a carrier frequency of 1/205 for the missense variant in this community (with no occurrence of the nonsense variant).

SLC35A3 is a nucleotide sugar transporter that transports (uniquely) UDP-N-acetylglucosamine (UDP-GlcNAc) from the cytoplasm where it is synthesized to its site of use in the Golgi. Proper function of such transporters is essential for biosynthesis of glycoproteins, glycolipids and proteoglycans.

Although the transport of UDP-GlcNAc is mediated also by other less specific transporters, members of the SLC35 family, reduced transport was shown in patient fibroblasts compared to controls. In addition an abnormal N-glycan profile was shown in patient fibroblasts (but was not the case in serum).

Biallelic SLC35A3 mutations in cattle were previously shown to cause a Complex Vertebral Malformation (CVM) syndrome characterized by abnormal growth, vertebral and heart malformations as well as arthrogryposis (Thomsen et al. - PMID: 16344554). Arthrogryposis as well as some skeletal features observed in patients were similar to those of the animal model.
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Marini et al. (PMID: 28328131) report on 2 sibs compound heterozygous for a missense and a frameshift variant [NM_012243.2:c.73C>T or p.(Arg25Cys) and c.899_900delTTinsA or p.(Leu300Glnfs*6)]. Hypotonia, DD with ID, early-onset seizures and arthrogryposis were features in both. Severe scoliosis was also noted in the younger sib.
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Edmondson et al. (PMID: 28777481) report on a neonate (follow-up till the 21st day of life) with extensive vertebral anomalies (butterfly vertebrae, hemibertebrae, sagittal clefts, scoliosis), heart defects (PFO, PDA) and arthrogryposis. Presence of hypotonia or other neurologic features (eg. seizures) is not commented on. Conventional caryotype and SNP-array analysis were normal apart from the presence of ROH regions due to parental consanguinity. Exome sequencing revealed only a homozygous missense SNV [c.74G>T or p.(Arg25Leu) - NP_036375.1] which was supported by an abnormal N-glycan profile. As proposed for the bovine model (PMID: 16344554) and discussed in this article, similarity of the skeletal/congenital heart defects with those observed in Alagille syndrome might be due to some of the Notch functions being dependent upon N-acetylglucosamine modification.
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In ClinVar :

There is a further submission of p.Ser296Gly as pathogenic (SCV000699337.1 - 2016) apart from the submission by OMIM (SCV000108589.2 - 2013). The associated condition is Arthrogryposis, mental retardation, and seizures.

A frameshift variant [NM_012243.2(SLC35A3):c.680dup (p.Asp227Glufs)- SCV000826704.1 - April 2018] as well as an intragenic deletion [NC_000001.10:g.(?_100472570)_(100477109_?)del (GRCh37) - SCV000837123.1 - June 2018] have both been submitted as pathogenic, associated with Arthrogryposis, mental retardation, and seizures. (Note: due to the different submission dates, one can presume that these variants were found in different individuals).
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SLC35A3 is not associated with any phenotype in G2P.
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As a result, this gene can be considered for inclusion in the epilepsy panel probably as green (or amber)
[Consider upgrade of this gene to green in other panels (eg. CDGs, arthrogryposis, IEMs) and/or inclusion in other possibly relevant panels.]
Sources: Literature

Created: 25 Dec 2018, 3:41 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Arthrogryposis, mental retardation, and seizures (MIM 615553)

Publications

• 24031089
• 28328131
• 28777481
• 16344554