Drop by drop Project

FRRB Project 3441133 - Deciphering the molecular signature in Kleefstra syndrome: proof of principle working model for chromatinopathies

The Coordinator of the project is ASST Ospedale Papa Giovanni XXIII. The Lead Principal Investigator of the project is Dr. Laura Pezzoli.

 Pathology:  Kleefstra Syndrome
 Tematic Area :  Neurology - Rare Diseases
 Project Start Date:  May 15, 2023
 Project End Date:  May 14, 2026
 Funding:  € 1.157.500,00
 Project Partners:  - ASST Ospedale Papa Giovanni XXIII
 - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
 - Università degli Studi di Milano


This proposal aims at developing in vitro tools for pharmacological screening of Kleefstra syndrome (KS) patients, applying different modeling systems based on phenotype and genotype classification.

KS is a rare genetic disorder caused by mutations in two genes (EHMT1 and KMT2C), encoding histone methyltransferases that regulate gene transcription. The phenotype is variable, and includes severe intellectual disability, hypotonia, brachy(micro)cephaly, seizures, heart defects, and typical facies.

Our proposal builds on a robust collaborative network and solid expertise with three specific aims:

AIM 1 - Classification of KS patients based on genotype and phenotype, through:

-      Setting up a Registry of the Italian KS patients to collect clinical data and natural history of the disease and implementing a biobank of immortalized lymphoblastoid cell lines (LCLs) (partner 1);

-      Characterizing KS genetic variants through breakpoints definition (for gross deletions) and gene expression study to stratify the patients based on pathophysiological mechanisms (coordinator).

AIM 2 - Testing drugs counteracting the detrimental effects of mutations in the patients' LCLs (partner 2).

AIM 3 - Modeling selected patient-specific mutations with 3D brain organoids for assessing ameliorative effects of drugs selected in aim 2 (partner 2).


The project will exploit the collaboration of the Italian Kleefstra Association, using state-of-the-art methods to pave the way for personalized medicine for rare genetic disorders.