Research Highlights KDM5C research project Representing the Signature Research Project of our P50-funded IDDRC, this program of research focuses on a single gene, lysine demethylase 5C (KDM5C), genetic variants which are observed in patients with the rare intellectual disability disorder (IDD) Claes-Jensen syndrome. The KDM5C gene encodes a protein that regulates gene expression by altering chromatin. However, it remains unknown how KDM5C regulates transcriptional programs that are critical for the development and activity of the brain. To understand this link, we use multi-OMICS approaches in animal models and human induced pluripotent stem cell (iPSC)-derived cerebral organoids. Fundamental insights gained from these studies will provide a mechanistic understanding of why variants in KDM5C cause cognitive impairment and are expected to highlight possible avenues for therapies for affected individuals. This program brings together a multi-disciplinary team of researchers who will integrate diverse analytical tools and model systems to understand KDM5C-induced ID. The research team is led by Dr. Julie Secombe, who has expertise in KDM5-mediated transcription and its relationship to ID using the animal model Drosophila melanogaster. Dr. Secombe works closely with Dr. Herb Lachman, whose interest in use of iPSCs and cerebral organoids enable us to analyze the function of KDM5C in a human neuronal context for the first time. Molecular studies using both Drosophila and iPSC-induced require the bioinformatic expertise of Dr. Deyou Zheng, permitting us to delve deeply into the transcriptional deficits caused by genetic variants in KDM5C. Complementing our Drosophila and human cell studies, Dr. Bryen Jordan will help test models of how variants in KDM5C alter cognition by using mouse models. To fully utilize model organism and human organoid data, it is critical to understand patient phenotypes. Dr. Lisa Shulman brings this expertise, as she is a developmental pediatrician who specializes in diagnosing and treating children with ASD and other developmental and learning disabilities. These studies make critical use of all four of the RFK IDDRC scientific cores (HCP, NGEN, NCEI and AP). The ultimate goal of this research is to help individuals with Claes-Jensen syndrome and their families. Drs. Secombe and Shulman have established a relationship with families of individuals with mutations in KDM5C through a Facebook support group and recently formed foundation. As seen in the accompanying photo, twelve of these families traveled from within the USA and from the UK in early 2020 to meet each other for the first time and attend Einstein IDDRC’s Rare Disease Day, which featured KDM5C research. Because the range of clinical features observed in those with genetic variants in KDM5C remain poorly described, this Rare Disease Day included a presentation of new data from 37 families in the Facebook group collected by Drs. Secombe and Shulman. These data have now been published1 and emphasize the variability in the severity of the cognitive and behavioral features seen in individuals heterozygous for variants in KDM5C. Further integration and analyses of genetic variant and clinical data from these families will greatly extend our understanding of Claes-Jensen syndrome. References: Hatch, H. A. M., O'Neil, M. H., Marion, R. W., Secombe, J. & Shulman, L. H. Caregiver-reported characteristics of children diagnosed with pathogenic variants in KDM5C. American journal of medical genetics. Part A, doi:10.1002/ajmg.a.62381 (2021). 22Q11.2DS Studies of rare genetic disorders with known etiologies can serve as models to understand the cause of more common disease. The 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge/velo-cardio-facial syndrome) occurs in 1/4000 live births and affected individuals have medical, cognitive and behavioral problems, which range from mild to severe. Our interests are to use human subjects and animal models to understand how genes on the 22q11.2 region and elsewhere in the genome affect phenotype. One project is to understand brain sensory processing to eventually link to molecular mechanisms, and another is to understand the genetics of why some affected individuals have severe, while others have mild presentations of medical and cognitive phenotypes. Both projects utilize the Montefiore Einstein Regional Center for 22q11.2 Deletion Syndrome, in which interdisciplinary care is provided to local populations in the Bronx or New York City.