Early onset or syndromic epilepsy

Gene: SAMHD1

Green List (high evidence)

AD Chilblain Lupus syndrome and AR Aicardi-Goutieres syndrome 5. AR AGS5 - No mention of epilepsy as symptom in OMIM. Papers mentioned on panel app: Rice et al, 2009 -no mention of patients phenotype including epilepsy. Haskell et al, 2018 - 4 year old, has seizures and other features fitting - compound het. Crow et al, 2015 - 39% of patients in this paper variably manifested with seizures - doesn't say which patients so may not be the 13% with SAMHD1 mutations. Al Mutairi et al, 2018 - 2 patients with novel hom variants in this gene (fs and splicing) - both had seizures.

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
?Chilblain lupus, 614415 AD; Aicardi-Goutieres syndrome, 612952

Publications

• 29239743

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: Green review plus Confirmed DD-G2P gene for Aicardi-Goutieres syndrome, which can present with seizures. 2 seizures reported in patients with SAMHD1 variants in PMID:29239743. Plus seizures are a common phenotype of AGS (PMID:29239743 and PMID:25604658), and since variants in SAMHD1 are a known cause of AGS, it is reasonable to include SAMHD1 on the panel. PMID:30275001 also provide support with one pathogenic and one VUS SAMHD1 variant reported in a Japanese girl with seizures.

Created: 8 Nov 2018, 9:06 a.m.

PMID:30275001 (Haskell et al 2018) report a 4 year old girl with global developmental delay and seizures. WES identified two candidate causative pathogenic variants in SAMHD1: c.602T>A p.I201N (previously reported as pathogenic) and c.1293A>T p.L431F (a VUS).

Created: 8 Nov 2018, 9:05 a.m.

Rice et al., 2009 (PMID:19525956): In 13 families from varying places (Hungarian, Maltese, French, Pakistani, Canadian, Moroccon, Indian, Arab, Ashenzai, Fijan) they identified homozygous or compound heterozygous variants in the SAMHD1 gene. Some families were consanguineous. Detailed phenotypes for the individuals were not listed.

Created: 8 Nov 2018, 9:05 a.m.

PMID:25604658 (Crow et al. 2015) reported on 374 patients from 299 families with symptoms including seizures in 140 patients. Biallelic SAMHD1 variants were recorded in 38 families, and one heterozygous SAMHD1 variant (p.Ile201Asn) was found in 1 family.

Created: 8 Nov 2018, 9:05 a.m.

PMID:29239743 (Mutairi et al., 2018) reviewed the records of 24 unrelated patients with Aicardi-Goutières syndrome from 6 tertiary hospitals in different Arab countries. The most common presenting signs were developmental delay and seizures. Homozygous c.205C>T variants in SAMHD1 were found in 2 cases, both of whom had seizures.

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

Green List (high evidence)

AGS is generally associated with a high risk of seizure disorders.

Created: 20 Aug 2018, 1:06 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Aicardi-Goutieres syndrome 5, MIM#612952

Publications

• 29239743

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