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Intellectual disability - microarray and sequencing v3.1563 METTL5 Eleanor Williams Tag gene-checked tag was added to gene: METTL5.
Intellectual disability - microarray and sequencing v3.1514 METTL5 Arina Puzriakova Tag for-review was removed from gene: METTL5.
Intellectual disability - microarray and sequencing v3.1510 METTL5 Sarah Leigh commented on gene: METTL5
Intellectual disability - microarray and sequencing v3.1509 METTL5 Arina Puzriakova Source Expert Review Green was added to METTL5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability - microarray and sequencing v3.499 METTL5 Arina Puzriakova Phenotypes for gene: METTL5 were changed from Autosomal-Recessive Intellectual Disability and Microcephaly; Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality to Intellectual developmental disorder, autosomal recessive 72, 618665
Intellectual disability - microarray and sequencing v3.498 METTL5 Arina Puzriakova Tag for-review tag was added to gene: METTL5.
Intellectual disability - microarray and sequencing v3.498 METTL5 Arina Puzriakova reviewed gene: METTL5: Rating: ; Mode of pathogenicity: None; Publications: 29302074, 31564433; Phenotypes: Intellectual developmental disorder, autosomal recessive 72, 618665; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 METTL5 Zornitza Stark reviewed gene: METTL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29302074, 31564433; Phenotypes: Intellectual developmental disorder, autosomal recessive 72, MIM# 618665; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1090 METTL5 Rebecca Foulger Classified gene: METTL5 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v2.1090 METTL5 Rebecca Foulger Added comment: Comment on list classification: METTL5 was added to the panel and rated Green by Konstantinos Varvagiannis. There are just sufficient (3) cases from the literature (siblings in PMID:29302074 plus 2 families in PMID:31564433), and animal models (mice and zebrafish) exhibit microcephaly similar to the human phenotype. However, the Gly61Asp variant found in the PMID:29302074 siblings is currently classed as VUS and PMID:31564433 failed to demonstrate a functional impact for this variant on the encoded protein.

METTL5 has been recently added (October 2019) to DD-G2P with a probable rating for 'Autosomal-Recessive Intellectual Disability and Microcephaly'. METTL5 is not yet associated with a disorder in OMIM. Given the uncertainty of the functional significance of the Gly61Asp variant, on balance an Amber rating is appropriate at this time, pending further cases or functional evidence.
Intellectual disability - microarray and sequencing v2.1090 METTL5 Rebecca Foulger Gene: mettl5 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v2.1089 METTL5 Rebecca Foulger 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
Intellectual disability - microarray and sequencing v2.1088 METTL5 Rebecca Foulger Phenotypes for gene: METTL5 were changed from Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality to Autosomal-Recessive Intellectual Disability and Microcephaly; Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality
Intellectual disability - microarray and sequencing v2.1047 METTL5 Konstantinos Varvagiannis edited their review of gene: METTL5: Set current diagnostic: yes
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).

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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).
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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