De novo variants in SUPT16H are associated with developmental delay, intellectual disability, epilepsy and facial dysmorphism
Authors: Mengqi Ma 1,2; Xiao Mao 3,4; Yiming Zheng 1,2; Shenzhao Lu 1,2
Affiliations: 1) Baylor College of Medicine, Houston, TX; 2) Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX; 3) National Health Commission Key Laboratory of Birth Defects Research, Prevention and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Hunan, China; 4) Department of Medical Genetics, Maternal and Child Health Hospital of Hunan Province, Hunan, China
Keywords: k. developmental disorders; z. cell growth
We identified two individuals from two families carrying de novo missense variants in SUPT16H. The patients exhibit global developmental delay, intellectual disability, epilepsy, facial dysmorphism and structural abnormalities of the brain. SUPT16H is conserved across species and encodes the large subunit of the FACT complex which functions as a nucleosome organizer during transcription. Bioinformatic predications from population genomics databases indicate that SUPT16H is highly constrained for loss-of-function variants in humans and both missense variants p.T171I and p.G808R have not been reported to date. We employed Drosophila to characterize these two variants. We show that loss of the fly orthologue, dre4, causesearly lethality. Tissue-specific RNAi-mediated knockdown of dre4 in the eye or wing disc leads to loss of eye and wing, respectively. RNAi-mediated knockdown in the nervous system also causes severe defects. Expression of the human reference SUPT16H transgene partially rescued the loss-of-function phenotypes in wing, eye and nervous system. However, the p.T171I or p.G808R variants are much less efficient at rescuing these phenotypes, indicating that they are partial loss-of-function alleles. We show that dre4 functions in a cell-autonomous manner, rather than in an endocrine fashion dependent on ecdysteroid production as previously proposed. Altogether, our data indicate that de novo loss-of-function variants in SUPT16H are associated with neurological features.