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Severe microcephaly

Gene: DNMT3A

No list

DNMT3A (DNA methyltransferase 3 alpha)
EnsemblGeneIds (GRCh38): ENSG00000119772
EnsemblGeneIds (GRCh37): ENSG00000119772
OMIM: 602769, Gene2Phenotype
DNMT3A is in 9 panels

2 reviews

Rachel Jones (GSTT)

Green List (high evidence)

A single paper, but they identified 3 unrelated individuals with de novo missense mutations within 3 amino acids of each other in a highly conserved domain of DNMT3A who all had microcephalic dwarfism and similar phenotypes. They went on to do functional analysis of one of the mutations in vitro showing that it impaired binding of methylated H3K36 and altered methylation of key developmental genes in patient cells, and they generated a mouse strain carrying the same alteration which exhibited phenotypic similarity to the human patients, which is the opposite phenotype to loss of function mutations of this gene.

Therefore there are 3 unrelated patients plus functional evidence, which meets the criteria for making this green.
Created: 15 Oct 2020, 10:34 a.m. | Last Modified: 15 Oct 2020, 10:34 a.m.
Panel Version: 2.27

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
618724 HEYN-SPROUL-JACKSON SYNDROME; HESJAS

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Three individuals reported, two with the same de novo missense variant. Postulated to be GOF as opposed to LOF variants in this gene which cause an overgrowth syndrome. Animal model supports pathogenicity.
Sources: Expert list
Created: 4 Sep 2020, 10:23 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
intellectual disability; microcephaly; short stature

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
Phenotypes
  • intellectual disability
  • microcephaly
  • short stature
OMIM
602769
Clinvar variants
Variants in DNMT3A
Penetrance
None
Publications
Panels with this gene

History Filter Activity

4 Sep 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Zornitza Stark (Australian Genomics)

gene: DNMT3A was added gene: DNMT3A was added to Severe microcephaly. Sources: Expert list Mode of inheritance for gene: DNMT3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DNMT3A were set to 30478443 Phenotypes for gene: DNMT3A were set to intellectual disability; microcephaly; short stature Review for gene: DNMT3A was set to GREEN gene: DNMT3A was marked as current diagnostic