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Intellectual disability - microarray and sequencing v2.1047 | METTL5 |
Konstantinos Varvagiannis gene: METTL5 was added gene: METTL5 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METTL5 were set to 29302074; http://doi.org/10.1016/j.ajhg.2019.09.007; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf Phenotypes for gene: METTL5 were set to Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality Penetrance for gene: METTL5 were set to Complete Review for gene: METTL5 was set to GREEN Added comment: [1] - PMID: 29302074 : In a WES/WGS study of 404 consanguineous families with two or more offspring affected by ID, Hu et al. identified two sibs homozygous for a METTL5 missense variant [NM_014168:c.182G>A / p.Gly61Asp]. These 2 subjects, born to first cousin parents from Iran, presented with early learning impairment, aggressive behaviour, severe microcephaly (-7SD and -8SD) and ID formally evaluated to be in the severe range. Sanger confirmation of variants and segregation studies were performed for all available and informative members in families participating in the study. In silico predictions were all in favour of a deleterious effect (PolyPhen2, MutationTaster, SIFT, CADD) and the variant was absent from ExAC. The effect of the specific variant was studied in ref. 2 (below). [2] - DOI: 10.1016/j.ajhg.2019.09.007 : Richard et al. (2019) reported on 5 additional individuals from 2 consanguineous families. Common phenotype consisted of speech delay, moderate/severe ID (4/4), microcephaly (4/4 - though milder than in the first report), behavioral problems (ADHD, aggressiveness, autistic feat.) and possibly some overlapping facial features (nose and ear abnormalities). 3 sibs from the 1st family, from Pakistan, were homozygous for a frameshift variant (NM_014167.2:c.344_345delGA / p.Arg115Asnfs*19) while sibs from the 2nd family, from Yemen, were homozygous for p.Lys191Valfs*1 (c.571_572delAA). Confirmation and segregation studies supported a role for the variants. The authors performed additional studies for METTL5 and all 3 variants reported to date, notably: - Based on RNA-seq data from the Allen Brain Atlas, METTL5 is expressed in the developing and adult human brain (incl. cerebellar cortex, hippocampus and striatum). - Immunostaining in mouse brain demonstrated ubiquitous expression (postnatal day 30). - In rat hippocampal neurons, enrichment of METTL5 was found in the soma, the nucleus and pre- and post- synaptic regions. - Myc-/GFP-tagged METTL5 wt or mutants were transiently expressed in COS7 cells, and were found in the cytoplasm and nucleus. Levels of the 2 frameshift variants were significantly reduced compared with wt, although this was not the case for Gly61Asp. - Upon transfection of rat hippocampal neurons, METTL5-GFP tagged wt and mt proteins showed similar localicalization in nucleus and dendrites. - Western blot on HEK293T cells transfected with Myc-METTL5 wt or mt constructs demonstrated decreased amounts for the frameshift (but not the missense) variants while comparison after addition of a proteasome inhibitor or cyclohexamide suggested that this is not probably due to decreased mutant protein - rather than mRNA (NMD) - stability. - In zebrafish, morpholino knockdown of mettl5 led to reduced head size and head/body ratio (reproducing the microcephaly phenotype) and curved tails. Forebrain and midbrain sizes were also significantly reduced. Based on the ACMG criteria, Gly61Asp is classified as VUS (PM2, PP1, PP3) and the frameshift ones as pathogenic (PS3, PM2, PM4, PP1, PP3). The authors comment that METTL5 is an uncharacterized member of the methyltransferase superfamily (of 33 METTL proteins). Variants in other methyltransferase-like genes (mainly METTL23) have been associated with ID, while various histone-/DNA-/tRNA-/rRNA- methyltransferases such as EHMT1, DNMT3A, NSUN2, FTSJ1, etc have been implicated in ID. Given the role of methyltransferases in neurodevelopment and neuroplasticity, homology comparisons suggesting presence of relevant domain in METTL5 and accumulation of the protein in the nucleus, a role as epigenetic regulator is proposed (see also ref. 3). [3] - Conference abstract by Helmut et al. ["A novel m6A RNA methyltransferase in mammals - characterization of Mettl5 mutant mice in the German Mouse Clinic" - Oral presentation in the 33rd International Mammalian Genome Conference Sept. 2019 - available at : https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf ] The group using an in vitro methyltransferase assay, identified METTL5 as a m6A RNA methyltransferase. Generation of Mettl5-knockout mice using the CRISPR/Cas technology, suggested that homozygous mice are subviable, with lower body mass and abnormal growth of nasal bones in half. Homozygous mice were hypoactive and hypoexploratory during an open field test at the age of 8 weeks, while further alterations were observed in neurological functions. Phenotypic deviations were absent or very mild in heterozygous animals. As a result, the mouse model appeared to recapitulate relevant human phenotypes (microcephaly, ID and growth retardation). ---- There is no associated entry in OMIM (neither for the gene nor for a related disorder). G2P does not list any phenotype for this gene, either. METTL5 is included in the SysID database as a current primary ID gene (cited: 27457812, 28097321 / Given the shared co-authors with the study by Richard et al. as well as the overlapping variants, these articles probably report on the same individuals recently described in more detail). The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). ---- Overall, METTL5 could be considered for inclusion in the ID panel probably as green (3 families, 3 variants, segregation, suggested role of the gene, relevant expression patterns, some evidence at the variant-level, zebrafish and mouse models) or amber (underlying effect of Gly61Asp unknown and variant classified as VUS). Sources: Literature |
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Intellectual disability - microarray and sequencing v2.682 | METTL23 | Ivone Leong Classified gene: METTL23 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.682 | METTL23 | Ivone Leong Added comment: Comment on list classification: METTL23 has been given a green gene rating based on the evidence provided by Konstantinos Varvagiannis (Other). There is enough evidence to support a gene-disease link. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.682 | METTL23 | Ivone Leong Gene: mettl23 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.681 | METTL23 | Ivone Leong Phenotypes for gene: METTL23 were changed from Mental retardation, autosomal recessive 44 (MIM 615942) to Mental retardation, autosomal recessive 44, 615942 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.579 | METTL23 |
Konstantinos Varvagiannis gene: METTL23 was added gene: METTL23 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: METTL23 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METTL23 were set to 24501276; 24626631 Phenotypes for gene: METTL23 were set to Mental retardation, autosomal recessive 44 (MIM 615942) Penetrance for gene: METTL23 were set to Complete Review for gene: METTL23 was set to GREEN gene: METTL23 was marked as current diagnostic Added comment: Biallelic pathogenic variants in METTL23 cause Mental retardation, autosomal recessive 44 (MIM 615942). Reiff et al. (PMID: 24501276) report on a consanguineous pedigree of Yemeni origin with 7 individuals presenting intellectual disability. Clinical details are provided for 3 subjects from one branch of the family. Findings included moderate (2/3) or severe (1/3) ID, seizures (2/3) and some common facial features. Seizures were not observed in individuals from other branch of the family. The affected individuals were homozygous for a 4-bp deletion. Bernkopf et al. (PMID: 24626631) report on a consanguineous family from Pakistan with 2 affected sibs as well as a non-consanguineous family from Austria with 4 affected sibs. The parents in the latter family originated from a small - geographically isolated - village. Individuals from the Pakistani family were homozygous for a nonsense variant, while the sibs from the Austrian family for a frameshift variant. Mild ID was noted in all. In total 3 different LoF variants have been reported. Extensive functional studies have been performed in both articles. METTL23 (methyltransferase like 23) is expressed at low-to-moderate levels in the developping human brain. Bernkopf et al. suggest that METTL23 is indeed a methyltransferase. The gene has 7 transcripts of which one is non-coding. 3 transcripts encode isoform 1 and 3 other encode isoform 2. The variant reported by Reiff et al. affects the coding region of 3 (of the 6 coding) transcripts (corresponding to isoform 1) and the 5'-UTR of the other 3 transcripts. It is however shown that this first coding exon (specific to isoform 1) is expressed in the developing human brain, though at lower levels than downstream exons common to both isoforms. In addition, only isoform 1 appears to be conserved in most other species. The variants described by Bernkopf et al. affect all 6 coding trancripts and as a result both isoforms. [However, the individuals reported by Bernkopf et al. were less severely affected compared to those reported by Reiff et al.] Nonsense-mediated decay appeared unlikely since mRNA levels for both isoforms in lymphoblasts from affected individuals were similar to controls (upon qRT-PCR) [The specific nonsense variant tested would be expected to be subject to NMD given its localization]. METTL23 is not associated with any phenotype in G2P. This gene is included in gene panels for intellectual disability offered by various diagnostic laboratories. As a result, METTL23 can be considered for inclusion in the ID panel as green (or amber). Sources: Literature |