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| Intellectual disability - microarray and sequencing v2.978 | PUS7 |
Catherine Snow Source Expert Review Green was added to PUS7. Source Expert Review was added to PUS7. Added phenotypes Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, 618342 for gene: PUS7 Publications for gene PUS7 were changed from to 30778726; 30526862 Rating Changed from No List (delete) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v2.853 | ALKBH8 |
Konstantinos Varvagiannis 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 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 |
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| Intellectual disability - microarray and sequencing v2.742 | PUS7 | Konstantinos Varvagiannis edited their review of gene: PUS7: Added comment: PMID: 30778726 (2019 - Shaheen et al.) reports 3 additional individuals from 2 consanguineous families. ID was a feature in all three. Variants reported: NM_019042.3 c.1507G>T or p.(Asp503Tyr) and c.329_332delCTGA or p.(Thr110Argfs*4), each found in homozygous state in affected individuals. As a result, PUS7 can be considered for inclusion in the ID panel as green. (The PMID for the article by de Brouwer et al. was added).; Changed publications: 30526862, 30778726 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.579 | PUS3 |
Konstantinos Varvagiannis gene: PUS3 was added gene: PUS3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: PUS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PUS3 were set to 27055666; 30308082 Phenotypes for gene: PUS3 were set to Global developmental delay; Intellectual disability; Microcephaly Penetrance for gene: PUS3 were set to Complete Review for gene: PUS3 was set to AMBER gene: PUS3 was marked as current diagnostic Added comment: PUS3 (Pseudouridylate synthase 3) is proposed as a gene related to ID in a recent publication on PUS7. Biallelic mutations in this gene are associated in OMIM with ?Mental retardation, autosomal recessive 55 (MIM 617051). PMID: 27055666 reports on 3 sisters from a consanguineous Saudi Arabian family with failure to thrive, DD/ID, microcephaly and some common (coarse) facial features. These individuals were homozygous for a stopgain mutation in the last exon of the gene. Pseudouridylation appeared to be defective (as has also been the case with other genes related to ID, eg. PUS7). PMID: 30308082 describes 1 individual born to consanguineous Palestinian parents, homozygous for a further LoF variant. Despite the localisation of this variant (again in the last exon of the gene) qPCR analyses were suggestive of degradation of the abnormal transcript possibly by NMD. The phenotype consisted of DD/ID and microcephaly. In a further publication (http://dx.doi.org/10.7124/bc.0008D6) Gulkovskyi et al. report on 2 siblings with ID, born to non-consanguineous Ukranian parents. Pathogenicity of the variant is disputed. [NM_031307.4:c.212A>G or p.(Tyr71Cys) is found in an apparent homozygous state in the sibs but was only found in their father. De novo occurence in the maternal allele is proposed although the possibility of microdeletion missed by aCGH or other plausible mechanisms are not considered. This variant has maximum pathogenicity scores in silico (not discussed) and has an allele frequency of 0.00006717 in gnomAD. The authors did not perform studies of pseudouridylation but examined for the presence of hypoproteinemia, observed in some disorders affecting this process). PUS3 is not associated with any phenotype in G2P but is associated with disease in OMIM. The gene is included in gene panels for ID offered by various diagnostic laboratories (including Radboudumc). PUS1 is included in the current panel as green and PUS7 has been suggested for inclusion. As a result, these gene can be considered for inclusion as amber (2 families) or green (given the supportive functional studies and/or the proposed role for the gene). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.579 | PUS7 | Konstantinos Varvagiannis reviewed gene: PUS7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, Microcephaly, Short stature, Behavioral abnormality; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.579 | PUS7 | Konstantinos Varvagiannis Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.579 | PUS7 |
Konstantinos Varvagiannis gene: PUS7 was added gene: PUS7 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PUS7 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PUS7 were set to Intellectual disability; Microcephaly; Short stature; Behavioral abnormality Penetrance for gene: PUS7 were set to Complete Review for gene: PUS7 was set to GREEN gene: PUS7 was marked as current diagnostic Added comment: de Brouwer et al. (https://doi.org/10.1016/j.ajhg.2018.10.026) report on 6 individuals from 3 unrelated families homozygous for truncating variants in PUS7. The common phenotype consisted of ID with speech delay, microcephaly, short stature as well as aggressive behavior. One frameshift, one nonsense and one intragenic deletion affecting the penultimate exon of PUS7 were private respectively to each family. qPCR demonstrated reduction of mRNA levels for the two first variants, with absence of the normally sized protein upon Western blot for the first one. The deletion, not identified due to its small size by aCGH, was found in the exome analysis and confirmed by MAQ. RT-PCR demonstrated the absence of the respective exon in mRNA. The deletion resulted in introduction of a stop codon in the last exon and mRNA expression levels were shown to be normal. Western blot demonstrated absence of a normally sized protein. (As a result, truncating mutations in the last exon may also be deleterious). Functional studies demonstrated defective tRNA and mRNA pseudouridylation. Drosophila knockouts recapitulated the behavioral phenotype. Biallelic mutations in PUS1 and PUS3 have been reported in individuals with intellectual disability (as well as some other features noted in PUS7-related disorder). PUS7 is included in the gene panel for ID offered by Radboud UMC (among the principal authors of the study). Therefore this gene can be considered for inclusion in this panel as green (rather than amber). Sources: Literature |
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