Early onset or syndromic epilepsy

Gene: SARS

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, noon | Last Modified: 11 Oct 2023, noon

Panel Version: 4.110

Comment on mode of inheritance: As only a single dominant case has been reported (details below), leaving MOI as biallelic for now with a watchlist_moi tag. Consider adding to other relevant panels if further cases are identified.

PMID: 36041817 - Single patient identified with de novo heterozygous splice site deletion (c.969_969+2delGGT) in the SARS1 gene. Phenotypes included complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Functional studies in both yeast strains and patient fibroblasts demonstrated a LoF, dominant negative effect.

Created: 7 Mar 2023, 2:26 p.m. | Last Modified: 7 Mar 2023, 2:27 p.m.

Panel Version: 3.100

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least three unrelated cases with biallelic variants in this gene - seizures detected in all families.

Created: 7 Mar 2023, 12:14 p.m. | Last Modified: 7 Mar 2023, 12:14 p.m.

Panel Version: 3.97

Third case identified by Bögershausen et al., 2022 (PMID: 35790048) with compound heterozygous variants in this gene, both inherited from each healthy parent. The proband displayed severe developmental delay, seizures, and severe microcephaly (HC −6.2 SD at 11 yrs old). Structural mapping showed the variant is located in the enzymes active site, likely diminishing activity, but no further functional studies were carried out.

Created: 7 Mar 2023, 12:13 p.m. | Last Modified: 7 Mar 2023, 12:13 p.m.

Panel Version: 3.96

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709

Publications

• 35790048
• 36041817

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. As there are only 2 cases there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.

Created: 13 Oct 2021, 1:41 p.m. | Last Modified: 13 Oct 2021, 1:41 p.m.

Panel Version: 3.1356

New gene name is SARS1

Created: 13 Oct 2021, 1:39 p.m. | Last Modified: 13 Oct 2021, 1:39 p.m.

Panel Version: 3.1355

I don't know

Summary - 2 unrelated families with overlapping ID phenotype, and supporting in vitro and patient cell assays.

PMID: 28236339 - an Iranian family (distantly related) segregating a homozygous missense (c.514G>A, p.Asp172Asn) with moderate ID, microcephaly, ataxia, speech impairment, and aggressive behaviour. Also, supporting in vitro functional assays demonstrating altered protein function.
PMID: 34570399 - a consanguineous Turkish family segregating a homozygous missense (c.638G>T, p.(Arg213Leu)) with developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death. Also, reduced protein level and enzymatic activity in patient cells.
Sources: Literature

Created: 11 Oct 2021, 9:44 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability

Publications

• 28236339
• 34570399