Severe microcephaly

Gene: DNMT3A

Green List (high evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 10 Mar 2022, 10:52 a.m. | Last Modified: 10 Mar 2022, 10:52 a.m.

Panel Version: 2.282

Associated with relevant phenotype (Heyn-Sproul-Jackson syndrome 618724) in OMIM and as probable Gen2Phen gene for Microcephalic primordial dwarfism. At least two gain of function variants reported in three unrelated cases, together with supportive functional studies (pmid 30478443).

Created: 24 Nov 2020, 12:32 p.m. | Last Modified: 24 Nov 2020, 12:32 p.m.

Panel Version: 2.46

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Note gain of function variants associated with this phenotype.

Created: 24 Nov 2020, 12:26 p.m. | Last Modified: 24 Nov 2020, 12:26 p.m.

Panel Version: 2.45

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

• PID: 30478443

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

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

• 30478443

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