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Genetic epilepsy syndromes

Gene: ALKBH8

Amber List (moderate evidence)

ALKBH8 (alkB homolog 8, tRNA methyltransferase)
EnsemblGeneIds (GRCh38): ENSG00000137760
EnsemblGeneIds (GRCh37): ENSG00000137760
OMIM: 613306, Gene2Phenotype
ALKBH8 is in 2 panels

4 reviews

Rebecca Foulger (Genomics England curator)

I don't know

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

Helen Lord (Oxford Medical Genetics Laboratories)

I don't know

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

Catherine Snow (Genomics England)

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

Konstantinos Varvagiannis (Other)

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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review
Phenotypes
  • Intellectual developmental disorder, autosomal recessive 71, 618504
  • Global developmental delay
  • Seizures
  • Intellectual Disability
  • Developmental Delay
  • Intellectual disability
OMIM
613306
Clinvar variants
Variants in ALKBH8
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

30 Sep 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: alkbh8 has been classified as Amber List (Moderate Evidence).

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to ALKBH8.

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to ALKBH8.

9 Sep 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

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

22 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

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)

2 Jun 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

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