"UNIQUE GENOME VARIANTS IN CONGENITAL NEURODEVELOPMENTAL DISORDERS: ORIGIN, GENOMIC MECHANISMS, FUNCTIONAL AND CLINICAL CONSEQUENCES"

Project acronym
UNIGENE

Project leader:
Prof. Vaidutis Kučinskas, Ph.D., Dr. habil.


Project will last for 41 months (November, 2012 – March, 2016).

Intellectual disability (ID) is one of the main disabling conditions in present day environment, and is thought to affect 1–3% of the population. It is a highly heterogeneous disorder, with the majority of cases having genetic etiology, which remain unexplained in 60 % of these cases. Recent advances in gene identification techniques have revolutionized the clinical approach to ID. The main aims of the proposed project are to detect novel genes mutations that cause ID, to determine their clinical significance in ID etiology and train a new generation of scientists in the process. The overall goal of this project is to establish a consortium bringing together experts in their respective fields to create an interdisciplinary program of activities that will increase our understanding of the etiology and pathophysiology of ID.  During the project we will use the most advanced techniques – will perform high resolution array CGH analysis in trios searching for novel chromosomal alterations; will also seek to identify candidate genes of ID by performing whole-exome sequencing in members of families with two affected sibs and a subset of trios. The advance that the proposed project will bring the discovering of the functional effect of the identified candidate genes using functional genomics approaches. Our Swiss partner has been in the forefront in the field of functional genomics for years will significantly contribute in achieving the main goals of this project. This novel and original approach for the investigation of candidate genes for ID will further contribute to other scientific investigations in Lithuania as our young researchers will be trained in the field of functional genomics. A straightforward outcome of the project will be the identification of single gene disorders that causes non-syndromic and syndromic ID, shedding light on the genes linked with newly identified syndromes and contributing for the development of novel therapeutic strategies.

Intellectual disability (ID) is a neurodevelopmental disorder described as substantial limitation in functioning that manifest before the age of 18 years. It is one of the main disabling conditions in present day environment, and is thought to affect 1–3% of the population. It is a highly heterogeneous disorder, with the majority of cases having genetic etiology. The possibilities of specific diagnosis and prevention are dependent on the search of genes associated with this disorder. Still it is very difficult to clinically recognize a specific genetic defect in any given patient with ID because of overlapping phenotypic spectra and heterogeneous etiology, and the genetic etiology in 60 % of these cases remain unexplained.
Recent advances in gene identification techniques have revolutionized the clinical approach to ID. When clinical features of the patient fail to trigger specific suspicion of diagnoses, genome-wide CNV detection and next-generation sequencing (NGS) approaches are effective tools to identify genes associated with ID by detecting causative chromosomal alterations and/or gene mutations. Exome sequencing has proved to be a powerful and cost-effective tool for dissecting the possible genetic basis of monogenic diseases and complex traits. Rare mutations that predispose to intellectual disability and other neurodevelopmental disorders such as autism spectrum disorders, schizophrenia, and epilepsy have recently been identified. Testing of unique samples from Lithuanian population by using high resolution whole genome analysis may aid in detection of new genetic causes of neurodevelopmental disorders. The partnership with Swiss scientists will contribute to the deeper understanding of the genetics of ID with the efforts to determine the functional effect of the identified candidate genes implicated in the neurodevelopmental processes. This project will be the first in-depth study of ID genes and their functions in Lithuania.


The main aims of the project are:

1. to detect novel genes mutations that cause ID,
2. to determine their clinical significance in ID pathogenesis
3. to train a new generation of scientists in the process.

The main objectives of the project will be:

1. Collection of biological material and clinical data of patients and relevant family members recruited according to the standardized selection criteria.
2. Detection of cryptic unique genomic rearrangements through high resolution molecular cytogenetic analysis.
3. Identification of causal genomic variants of neurodevelopmental disorders and detailed delineation of the selected chromosomal rearrangements using NGS approaches.
4. Establishment of bioinformatics workflow for high throughput data management and analysis for the array CGH, NGS and expression data, and identification of candidate genes potentially significant in neurodevelopmental processes for further characterization through functional genomics techniques.
5. Application of functional genomics approaches in order to confirm the candidate genes for neurodevelopmental disorders and expand the knowledge about their expression patterns, functions and interactions of the encoded proteins.
6. Delineation of the phenotypes in patients with unique genomic rearrangements and search for that disorder in larger cohorts through collaborative efforts.