Thread by @jakphd

Next up in the #ASHG21 late breaking plenary session is Elisa De Franco (@Elisa_EDF) presenting loss of primate-specific gene ZNF808.

#ASHG21 @Elisa_EDF: studying mice can provide insights into human biology, but there are differences. Mice have 2 genes for insulin (Ins1, Ins2), humans have 1 (INS).

#ASHG21 @Elisa_EDF: looked at 2877 neonatal diabetes patients from 111 countries and want Identify genes with pancreatic genesis.

#ASHG21 @Elisa_EDF: performed exome seq on 2 consanguineous families and found homozygous LoF in ZNF808 in both probands (1 with a stop gained variant, other with a CNV deletion).

#ASHG21 @Elisa_EDF: Replication in 232 neonatal diabetes probands. Found 11 probands with homozygous LoF in ZNF808, many showing loss in the last portion of ZNF808.

ZNF80 is a primate-specific KRAB-Zinc Finger transcription factor that targets transposable elements

#ASHG21 @Elisa_EDF: All other known genes involved in pancreatic developmental are more conserved than ZNF808.

What does ZNF808 do in human pancreatic development?

#ASHG21 @Elisa_EDF: In hESCs, loss of ZNF808 results in loss of repression of transposable elements and some are aberrantly activated.

#ASHG21 @Elisa_EDF: Transcriptome analysis shows that these cells with deleted ZNF808 often fail to develop into pancreatic cells. Appears this gene is essential to regulate the fate of cells developing into either pancreatic or liver cells.

#ASHG21: A good question asked whether heterozygous pLoFs in ZNF808 was also associated with diabetes later in life. Seems like a great use of the UKB 450k or just check it out in genebass.org!

Spoiler: nothing significant going on there.