Early onset or syndromic epilepsy

Gene: RNASEH2C

Green List (high evidence)

A further 37 patients (11.4%) (13 TREX1, one RNASEH2A, nine RNASEH2B, seven RNASEH2C, six SAMHD1, one ADAR) demonstrated neurological features at birth in the absence of obvious systemic features. (PMID:25604658). AR Aicardi Goutieres syndrome 3. Vogt et al 2013 - 2 pakistani sisters - no mention of seizures. Muitari et al, 2018 - 2 patients with a hom variant - both had seizures. Rice et al 2007. Like SAMHD1 mutations reported in Crow et al, 2015 - paper but don't know of the patients with this variant also have seizures?? Hebbar et al, 2018 - 3 Indian families (4 individuals - all had seizures and a hom missense variant -thought to be founder mutation.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Aicardi-Goutieres syndrome, 610329

Publications

• 25604658

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on list classification: Updated rating from Amber to Green: Confirmed DD-G2P gene for Aicardi-Goutieres syndrome 3, which can present with seizures. Most AGS patients carry the c.205C>T variant, which has been characterized as Founder effect in Pakistani patients (PMID:29150899). Additional variants are observed in single families (PMID:25604658 and PMID:20131292). Although it's unclear in some papers whether the AGS patients specifically with RNASEH2C variants displayed seizures, RNASEH2C variants are a known cause of AGS, and seizures are a common feature of AGS; therefore it is reasonable to include RNASEH2C on the Genetic Epilepsy panel.

Created: 8 Nov 2018, 9:04 a.m.

PMID:29239743 (Mutairi et al., 2018) reviewed the records of 24 unrelated Arab patients with Aicardi-Goutières syndrome. The most common presenting signs were developmental delay and seizures. Homozygous c.205C>T variants in RNASEH2C were found in 2 cases, both of whom had seizures.

Rice et al 2007 (PMID:17846997) collected clinical data for 123 individuals from 94 families with variants in TREX1, RNASEH2A, RNASEH2B, or RNASEH2C. 2 individuals who presented at birth had RNASEH2C variants and experienced neonatal seizures (Table 2).

PMID:25604658 (Crow et al. 2015) reported on 374 patients from 299 families with symptoms including seizures in 140 patients. 35 families had RNASEH2C variants.

PMID:29150899 (Hebbar et al 2018) identify a founder variant (c.205C>T (NM_032193.3, p.Arg69Trp) in RNASEH2C in three Indian families (4 patients) with AGS. All patients had seizures and neurodevelopmental delay. This variants contributes to 72% of cases with AGS type 3. Other variants are observed in single families (PMID:25604658 and PMID:20131292).

Created: 8 Nov 2018, 9:02 a.m.

Green List (high evidence)

Seizures are part of the phenotype of this neurological disorder.

Created: 20 Aug 2018, 10:33 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Aicardi-Goutieres syndrome 3, MIM#610329

Variants in this GENE are reported as part of current diagnostic practice