Severe microcephalyGene: METTL5
Comment on list classification: Borderline Green/Amber gene. Sufficient unrelated cases (3) from literature and supportive animal models, but uncertain functional significance of one variant. Thus METTL5 will be flagged for review of evidence at the next GMS panel update (added 'for-review' tag)
Created: 28 Oct 2020, 4:21 p.m. | Last Modified: 28 Oct 2020, 4:21 p.m.
Panel Version: 2.40
Associated with 'Intellectual developmental disorder' in OMIM, and is a 'probable' gene for 'Autosomal-Recessive Intellectual Disability and Microcephaly' in DD-G2P.
Gene added and expert reviewed on Intellectual Disability panel: https://panelapp.genomicsengland.co.uk/panels/285/gene/METTL5/
Distinct biallelic variants reported in 3 unrelated families (total 9 individuals) with severe microcephaly (OFC -2.8 to -8 SD) and intellectual disability. Mouse and zebrafish models appeared to recapitulate relevant human phenotypes (microcephaly, ID and growth retardation).
However, the Gly61Asp variant found in the PMID:29302074 siblings is currently classified VUS as localisation and expression studies failed to demonstrate a functional impact on the encoded protein.
Created: 28 Oct 2020, 4:15 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Intellectual developmental disorder, autosomal recessive 72, 618665
Gene: mettl5 has been classified as Amber List (Moderate Evidence).
gene: METTL5 was added gene: METTL5 was added to Severe microcephaly. Sources: Literature for-review tags were added to gene: METTL5. Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METTL5 were set to 29302074; 31564433; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf Phenotypes for gene: METTL5 were set to Intellectual developmental disorder, autosomal recessive 72, 618665