Early onset or syndromic epilepsy

Gene: ALKBH8

Green List (high evidence)

Gene was reassessed following a recent amber review by Helen Lord. To date, at least 12 individuals from 5 unrelated families have been reported in literature with homozygous variants in the ALKBH8 gene (PMIDs: 31079898; 33544954; 34757492; 35571055). All has DD/ID and 8 patients (from different 4 families) had seizures and therefore it is feasible that cases may be tested under this panel. Overall this support the Green gene rating on this panel.

Created: 10 Aug 2022, 10:16 a.m. | Last Modified: 10 Aug 2022, 10:16 a.m.

Panel Version: 2.563

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual developmental disorder, autosomal recessive 71, OMIM:618504

Publications

• 31079898
• 33544954
• 34757492
• 35571055

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

Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.

Panel Version: 2.491

Green List (high evidence)

This gene is rated Green on the ID panel based on the same evidence. 6/7 reported individuals had seizures, so seizures are a consistent feature of the phenotype of this neurodevelopmental phenotype.

Created: 28 Jan 2020, 10:01 a.m. | Last Modified: 28 Jan 2020, 10:01 a.m.

Panel Version: 2.0

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual developmental disorder, autosomal recessive 71, MIM# 618504

Publications

• 31079898

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

I don't know

Kept rating as Amber following advice from the Genomics England Clinical Team since Amber was the GLH opinion. This is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Have added 'for-review' tag to highlight the Green review from Zornitza. Note that Zornitza's review focuses on the differing ratings of ALKBH8 on the ID and Epilepsy panels, which I will align for consistency: no new evidence in the review.

Created: 19 May 2020, 4:13 p.m. | Last Modified: 19 May 2020, 4:13 p.m.

Panel Version: 2.56

Comment on list classification: Demoted ALKBH8 from Green to Amber following review from Helen Lord on behalf of West Midlands, Oxford and Wessex GLH, and agreement from Richard Scott (Genomics England clinical team).

Created: 30 Sep 2019, 3:11 p.m. | Last Modified: 30 Sep 2019, 3:11 p.m.

Panel Version: 1.347

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

I don't know

Saad et al, 2021: Third family of Egyptian descent harbouring a novel homozygous fs variant in the last exon of ALKBH8 - seen in two affected siblings, unaffected parents are het carriers. Parents are consanguineous. Variant likely to escape NMD.
Both proband and aff sister had global dev delay, autisitic features, - neither have epilepy or seizure-like episodes. Do have structural brain abnormalities including mild-mod cerebral volume loss, mild to mod cerebellar vermian hypoplasia, variable degrees of thinning of the corpus callosum and abnormal myelination for age on brain MRI.

Still would classify as amber...

Created: 27 Apr 2022, 8:39 a.m. | Last Modified: 27 Apr 2022, 8:39 a.m.

Panel Version: 2.518

AR MRT71. Monies et al, 2019 (31079898 & 31130284) - 7 patients from 2 unrelated consang Saudi kindreds. 6/7 developed seizures in first year of life but all well controlled. Hom LOF variants were identiifed. Have done some work looking at wobble modifications - not sure if this is enough evidence to make a green gene.

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

Phenotypes
Neurodevelopmental disorders

Publications

• 33544954

Green List (high evidence)

ALKBH8 had been identified by Genomic England curator when article was in press. Requested clinical team for support on rating on ID panel, clinical team advised "there are 7 affected individuals from two families with different LOF variants. They all have ID / GDD. There has been some functional work to indicate a lack of gene function in support. On balance I think this just meets our criteria for a green rating. 6/7 had seizures too so probably worth adding there too."

Created: 19 Jun 2019, 11:12 a.m. | Last Modified: 22 Jul 2019, 3:05 p.m.

Panel Version: 1.178

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 31079898

I don't know

Monies et al. (2019 - PMID: 31079898) report on 7 individuals from 2 different consanguineous Saoudi families, harboring homozygous truncating ALKBH8 pathogenic variants. The same individuals are included in another concurrent publication from the same group (Monies et al. 2019 - PMID: 31130284).

All presented with DD and ID (Fam1 : moderate in the proband, degree not commented on for his 3 sibs / Fam2 : mild in the proband, severe in all his 3 sibs). Epilepsy was reported for 6/7 individuals although the type has not been commented on (onset 9-12 months to 2 years). Variable other features were noted in few.

Affected subjects from the first family were homozygous for a stopgain variant (NM_001301010.1:c.1660C>T or p.Arg554Ter) while individuals from the second family were homozygous for a frameshift one (c.1794delC or p.Trp599Glyfs*19). The variants affected in both cases the last exon of ALKBH8 and RT-PCR confirmed that they escape NMD.

Alternative causes were ruled out, at least for the proband from the second family (chromosomal analysis, SNP-array, metabolic investigations).

Linkage analysis of both families confirmed linkage to the same autozygous interval of chr11q22.3 with a LOD score of 6.

Segregation analyses in both families, confirmed homozygosity for the truncating variants in affected members and heterozygosity in their parents (or several unaffected sibs, none of those studied was homozygous for the ref. allele).

In mouse or human cells, ALKBH8 has previously been shown to be involved in tRNA modifications of the wobble uridines of specific tRNAs (PMIDs cited: 20308323, 20583019, 21653555).

LC-MS/MS analyses of tRNA extracted from LCLs derived from affected individuals, unaffected relatives (UR) and independent controls (IC) revealed that wobble nucleotide modifications were completely absent (or dramatically decreased in the case of mcm5U) in affected individuals but readily detected in UR/IC. As specific modifications were absent, substantial amounts of precursors (eg. cm5U - the precursor of mcm5U) were detected in affected individuals but not in unaffected ones.

Absence of wobble modifications (eg. mchm5U) has equally been observed in Alkbh8 knockout mice. Alkbh8-deficient mice show similar increases in precursors. Alkbh8 KO mice are however phenotypically normal (the authors comment that eventual cognitive defects were not formally evaluated and might have been missed - PMIDs cited: 20123966, 21285950).

As a result, the studies carried out confirmed the loss-of-function effect and were in line with previous functional studies in animal models, although the pathogenesis of ID remains unclear.

The expression profile of ALKBH8 is also unclear (wide profile of expression suggested developmentally, the authors studied LCLs, other studies suggest that embryonic expression is broad but becomes progressively more restricted to specific neuronal cells).

Mutations in other genes involved in tRNA modification (eg. ADAT3, PUS3, PUS7) have been shown underlie disorders affecting the CNS, with ID as a feature.

ALKBH8 is not currently associated with any phenotype in OMIM / G2P.

As a result, this gene can be considered for inclusion in the ID/epilepsy panels as amber pending further evidence.
Sources: Literature

Created: 2 Jun 2019, 12:16 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Seizures

Publications

• 31079898