Improved diagnosis of paediatric mental retardation
Intellectual disability (ID) is a neurodevelopmental disorder that affects 1–3 % of the population and is characterised by a substantial limitation in cognitive functioning. Nearly half of the cases are of genetic origin and retardation manifests before the age of 18 years. Any possibility for early diagnosis or prevention is dependent on the identification of gene defects and chromosome abnormalities associated with this disorder. Based on this, the EU-funded Cherish project aimed to contribute to the diagnostic investigation of affected children in countries involved through genetic testing. Through an interdisciplinary consortium of experts, the overall goal of the project was to develop a standardised approach for clinical diagnosis of ID and through a clinical biobank to identify cryptic chromosomal rearrangements, mutations and genes responsible for the disorder. To this end, researchers performed whole genome array-comparative genomic hybridisation (CGH) and single nucleotide polymorphism (SNP) analyses in blood samples from patients and family members. Many cryptic rearrangements were detected by CGH in patients where conventional karyotyping, targeted FISH, molecular tests and investigations for metabolic disorders had failed to reveal any causative anomalies in the past. This clearly indicated that the Cherish-proposed technologies could significantly improve current molecular diagnosis of ID. Copy number variations (CNVs) were screened against databases of national general populations, and the potential clinical significance of CNVs not present in non-affected individuals was evaluated using OMIM and DECIPHER databases. With respect to ID causative genes, two genes involved in small interstitial deletion (CADPS2 on chromosome 7q31 and PCDH18 on chromosome 4q28) were considered excellent candidates and were used for further studies. Affected individuals from families with ID were selected for whole exome sequencing (WES) to analyse almost all the known exons (protein-coding gene portions) of ID-causing genes. This method offers the advantage of speeding up the molecular diagnosis of heterogeneous genetic disorders such as ID. By applying different state-of-the-art methodologies, the Cherish consortium succeeded in characterising the genetic basis of various forms of ID while providing novel means for diagnosis. The work is expected to increase awareness on the possible genetic origin of ID and the beneficial implications of novel therapeutic strategies.
