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Early onset or syndromic epilepsy v2.564 ALKBH8 Arina Puzriakova Publications for gene: ALKBH8 were set to 31130284; 31079898
Early onset or syndromic epilepsy v2.563 ALKBH8 Arina Puzriakova reviewed gene: ALKBH8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079898, 33544954, 34757492, 35571055; Phenotypes: Intellectual developmental disorder, autosomal recessive 71, OMIM:618504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.518 ALKBH8 Helen Lord edited their review of gene: ALKBH8: Added comment: 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...; Changed publications to: 33544954; Changed phenotypes to: Neurodevelopmental disorders
Early onset or syndromic epilepsy v2.491 ALKBH8 Sarah Leigh Tag for-review was removed from gene: ALKBH8.
Early onset or syndromic epilepsy v2.491 ALKBH8 Sarah Leigh commented on gene: ALKBH8
Early onset or syndromic epilepsy v2.490 ALKBH8 Sarah Leigh Source Expert Review Green was added to ALKBH8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.376 ALKBH8 Arina Puzriakova Phenotypes for gene: ALKBH8 were changed from Intellectual developmental disorder, autosomal recessive 71, 618504; Global developmental delay; Seizures; Intellectual Disability; Developmental Delay; Intellectual disability to Intellectual developmental disorder, autosomal recessive 71, OMIM:618504
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger Tag for-review tag was added to gene: ALKBH8.
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger commented on gene: ALKBH8: 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.
Early onset or syndromic epilepsy v2.0 ALKBH8 Zornitza Stark reviewed gene: ALKBH8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079898; Phenotypes: Intellectual developmental disorder, autosomal recessive 71, MIM# 618504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v1.347 ALKBH8 Rebecca Foulger Classified gene: ALKBH8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.347 ALKBH8 Rebecca Foulger Added comment: 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).
Early onset or syndromic epilepsy v1.347 ALKBH8 Rebecca Foulger Gene: alkbh8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.331 ALKBH8 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALKBH8.
Early onset or syndromic epilepsy v1.330 ALKBH8 Rebecca Foulger Source NHS GMS was added to ALKBH8.
Early onset or syndromic epilepsy v1.309 ALKBH8 Rebecca Foulger Phenotypes for gene: ALKBH8 were changed from Global developmental delay; Seizures; Intellectual Disability; Developmental Delay; Intellectual disability to Intellectual developmental disorder, autosomal recessive 71, 618504; Global developmental delay; Seizures; Intellectual Disability; Developmental Delay; Intellectual disability
Early onset or syndromic epilepsy v1.262 ALKBH8 Rebecca Foulger reviewed gene: ALKBH8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.261 ALKBH8 Helen Lord reviewed gene: ALKBH8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.178 ALKBH8 Catherine Snow edited their review of gene: ALKBH8: Changed rating: GREEN
Early onset or syndromic epilepsy v1.178 ALKBH8 Catherine Snow changed review comment from: Expert review by Konstantinos Varvagiannis on ALKBH8. Monies et al. (2019 - PMID: 31079898) report on 7 individuals from 2 different consanguineous Saudi 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).

Epilepsy was reported for 6/7 individuals although the type has not been commented on (onset 9-12 months to 2 years). Variable other phenotype features were noted in few.

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


ALKBH8 can be included in the epilepsy panel as Amber awaiting further evidence and tagged on the watchlist.; to: 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."
Early onset or syndromic epilepsy v1.177 ALKBH8 Catherine Snow Source Expert Review Green was added to ALKBH8.
Source Expert Review was added to ALKBH8.
Added phenotypes Seizures; Developmental Delay; Intellectual Disability for gene: ALKBH8
Publications for gene ALKBH8 were changed from 31079898 to 31130284; 31079898
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.62 ALKBH8 Catherine Snow commented on gene: ALKBH8: Expert review by Konstantinos Varvagiannis on ALKBH8. Monies et al. (2019 - PMID: 31079898) report on 7 individuals from 2 different consanguineous Saudi 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).

Epilepsy was reported for 6/7 individuals although the type has not been commented on (onset 9-12 months to 2 years). Variable other phenotype features were noted in few.

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


ALKBH8 can be included in the epilepsy panel as Amber awaiting further evidence and tagged on the watchlist.
Early onset or syndromic epilepsy v1.62 ALKBH8 Catherine Snow reviewed gene: ALKBH8: Rating: AMBER; Mode of pathogenicity: None; Publications: 31079898; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.52 ALKBH8 Konstantinos Varvagiannis gene: ALKBH8 was added
gene: ALKBH8 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ALKBH8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALKBH8 were set to 31079898
Phenotypes for gene: ALKBH8 were set to Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: ALKBH8 were set to Complete
Review for gene: ALKBH8 was set to AMBER
Added comment: 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