Perria, Chiara (2016) Whole exome sequencing in neurodevelopmental disorders: study of 10 families of Sardinian origin. Doctoral Thesis.
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Intellectual disability (ID) represents a large and heterogeneous group of disorders with variable phenotypes and severity. The genetic aetiology of the 60% forms remains unexplained. Here we aimed to identify new genetic causes of autosomal recessive ID forms by using the Whole Exome Sequencing (WES) approach.
We selected 10 Sardinian families, with at least 2 patients affected by Multiple Congenital Anomalies and ID. The clinical description of each patient was reported using the terminology of Human Phenotype Ontology. We used the Illumina technology for WES.
We identified mutations in 2 out of the 10 families studied; a CKAP2L mutation in a family with Filippi Syndrome, and a CREBBP mutation in another family, leading to the Rubinstein-Taybi syndrome. Variants identified in 5 more families are under investigation to determine their implication in the phenotype. The search for candidate variants is ongoing for the remaining families.
The success rate of our WES is 20%, in line with that reported in literature (25-30%). WES may be the most cost-effective way to reach a diagnosis and guide appropriate management by significantly reducing the time and cost to diagnosis, but still remain significant challenges.
Negative results where a diagnosis was not reached may be due to technical and scientific limitations or patient selection bias. To improve clinical and cost outcomes, diagnostic algorithms that include WES testing need to be created and implemented in the near future.
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