Thread by @ksamocha

Maureen Pittman #ASHG22: Oligogenic inheritance describes situations were there are some loci (more than one, less than thousands) that contribute to a disease.

Congenital heart disease (CHD) is potentially one of these situations.

Maureen Pittman #ASHG22: Example of a family where GATA6 was passed on from an unaffected parent to a child with CHD. Common variants don't seem to contribute much -- could it be due to other rare variants?

Maureen Pittman #ASHG22: Oligogenic genes are presumed to have related functions and could potentially compensate for each other or could interact, etc.

But finding oligogenic gene examples has been hard due to all of the combinations you have to test.

Maureen Pittman #ASHG22: Want to use parent genotypes to establish how often certain pairs of variants should appear in the child. GCOD (gene combinations in oligogenic disease) algorithm.

Using 3.3k cases in pediatrics cardiac genomics consortium.

Maureen Pittman #ASHG22: Can make simulated offspring datasets to compare the rare predicted damaging variant combinations to what you'd see in a null simulation. ("family-by-gene matrix simulations")

Then can evaluate if there is significant overtransmission.

Maureen Pittman #ASHG22: GCOD network pulls out genes explicitly related to heart structure or indirectly related to heart development.

Maureen Pittman #ASHG22: Looking at a large protein complex network from CREBBP and EP300 pair.

Maureen Pittman #ASHG22: What were the most improbable pairs?

GCOD predicts and interaction between GATA6 and POR. Three probands but all of them were a combination of one inherited variants + a de novo.

Maureen Pittman #ASHG22: GATA6 and POR knockdowns show interactions in mouse heart development -- seeing half with atrial septal defect.

(As an aside, Maureen is handling the mouse struggles with grace. Particularly love the "we're doing it" quip.) #ASHG22

Maureen Pittman #ASHG22: Can read more about the work in the preprint:
biorxiv.org/content/10.110…