Intellectual disability
Gene: ALKBH8
Gene was reassessed following a recent review by Konstantinos Varvagiannis indicating a rating upgrade to Green may be warranted. 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 patients displayed DD/ID as the predominant feature of their phenotype and therefore the evidence supports a Green gene rating on this panel.Created: 10 Aug 2022, 10:20 a.m. | Last Modified: 10 Aug 2022, 10:20 a.m.
Panel Version: 3.1659
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Intellectual developmental disorder, autosomal recessive 71, OMIM:618504
Publications
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Comment on list classification: This gene has been promoted back to Green status to reflect the rating that was on the signed off version of this panel (version 3.2). This gene should be demoted to Amber at the next review.Created: 14 Jan 2021, 10:42 a.m. | Last Modified: 14 Jan 2021, 10:42 a.m.
Panel Version: 3.703
Comment on list classification: Demoted from Green to Amber based on advice from the Genomics England Clinical Team. In email correspondence, Helen Brittain notes that this is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Zornitza's review on the Genetic Epilepsy Syndromes panel focuses on the differing ratings of ALKBH8 on the ID (Green) and Epilepsy (Amber) panels. Based on borderline evidence, I have demoted ALKBH8 to Amber on the ID panel to be consistent with the GLH consensus on the Epilepsy panel (R59 #402).Created: 19 May 2020, 4:17 p.m. | Last Modified: 19 May 2020, 4:17 p.m.
Panel Version: 3.66
Two families, different LOF mutations, with evidence of functional impairment of the gene and a relevant phenotype. On this basis I would include it as green, although borderline. This can be reviewed in the light of any new evidence.Created: 19 Jul 2019, 9:28 a.m. | Last Modified: 19 Jul 2019, 9:28 a.m.
Panel Version: 0.202
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Comment on list classification: ALKBH8 had been identified by Genomic England curator when article was in press. Requested clinical team for support on rating they 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: 24 Jun 2019, 3:48 p.m. | Last Modified: 24 Jun 2019, 3:48 p.m.
Panel Version: 0.193
Expert review by Konstantinos Varvagiannis on ALKBH8. Monies et al. (2019 - PMID: 31079898) report on 7 individuals from 2 different consanguineous Saudi families,
The individuals all had homozygous truncating ALKBH8 pathogenic variants.
All individuals had DD and ID.
ALKBH8 is not currently associated with any phenotype in OMIM / G2P.
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. ADAT3 is green on ID panel and PUS3, PUS7 have been proposed to included on the ID panel.
ALKBH8 can be included in the ID panel as Amber awaiting further evidence and tagged on the watchlist.Created: 12 Jun 2019, 2:47 p.m. | Last Modified: 24 Jun 2019, 3:44 p.m.
Panel Version: 0.192
Please consider upgrade to green rating.
2 additional relevant families reported in literature, as summarized below. While affected individuals from 3 (of the 4 total) families with the disorder were homozygous for truncating variants in the last exon (potentially corresponding to hypomorphic / incomplete LoF rather than null alleles), a more recent publication describes 2 sibs homozygous for a missense SNV with demonstrated loss-of-function in the context of normal protein levels.
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Saad et al (2020 - PMID: 33544954) report 2 sibs, born to consanguineous parents from Egypt homozygous for an ALKBH8 frameshift variant. Both exhibited global DD and ID (proband IQ of 51 / Stanford Binet test, sib: 42 using Weschler scale). There was no history of seizures. Family based exome sequencing of both sibs and parents revealed homozygosity for NM_001301010.1:c.1684delC [p.(Arg562Alafs*56))] within a region of AOH. As the authors note this variant also occurred in the last exon of the gene, likely escaping NMD and based on previous evidence from Monnies et al, hypothesize that truncating variants in the last exon represent hypomorphic alleles encoding for a partially functional protein, while protein truncating variants in earlier exons may be null alleles.
Maddirevula et al (2021 - PMID: 34757492) describe the phenotype of 2 sibs, homozygous for a missense variant. Features included severe DD and ID, microcephaly, facial dysmorphism and epilepsy (the latter limited to the elder one). Exome with autozygome analysis identified homozygosity for a missense variant (NM_138775.2:c.1874G>A / p.Arg625His) with Sanger for confirmation / segregation studies.LC-MS/MS using tRNA isolated from LCLs from the affected individual, a carrier parent and controls revealed complete loss of ALKBH8-dependent tRNA posttranscriptional modifications, the results being suggestive of abrogation of the catalytic activities of both MT and Ox domains. The protein was detected at low levels in LCLs from control and patient samples, a finding that was also supported by immunoblot analysis suggesting that the observed loss-of-function is not mediated by loss of the protein.Created: 28 May 2022, 1:11 p.m. | Last Modified: 28 May 2022, 1:11 p.m.
Panel Version: 3.1593
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: LiteratureCreated: 2 Jun 2019, 12:14 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Global developmental delay; Intellectual disability; Seizures
Publications
Publications for gene: ALKBH8 were set to 31130284; 31079898; 33544954; 34757492
Tag Q3_22_rating tag was added to gene: ALKBH8.
Publications for gene: ALKBH8 were set to 31130284; 31079898
Tag for-review was removed from gene: ALKBH8.
Source Expert Review Amber was added to ALKBH8. Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Phenotypes for gene: ALKBH8 were changed from Global developmental delay; Seizures; Intellectual disability to Intellectual developmental disorder, autosomal recessive 71, OMIM:618504
Gene: alkbh8 has been classified as Green List (High Evidence).
Tag for-review tag was added to gene: ALKBH8.
Gene: alkbh8 has been classified as Amber List (Moderate Evidence).
Source Expert Review Green was added to ALKBH8. Source Expert Review was added to ALKBH8. Added phenotypes Global developmental delay; Seizures; 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)
Publications for gene: ALKBH8 were set to
gene: ALKBH8 was added gene: ALKBH8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ALKBH8 was set to BIALLELIC, autosomal or pseudoautosomal 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