Deciphering the genetic basis of intellectual disability through unbiased genomic approaches
Year: 2017
Type: dissertation
Study design: Observational Study
Abstract: Neurodevelopmental disorders arise in childhood and are life-long condition that represents many challenges to the patients, their families and society, through public services. Among those, intellectual disability affects 1% of the population in developed countries, encompassing the most common group of neurodevelopmental disorders. Intellectual disability is characterized by cognitive impairment and limitation in functioning capacity and can be cause by exogenous factors (such as maternal alcohol abuse during pregnancy, infections and malnutrition) but it is well established that genetic factors play important roles in its pathophysiology. In ID, as in many others disorders, detecting the underlying genetic cause is a complex and time consuming process yet of great value to the patients and families because it allows the possibility of genetic counseling. In the last years, advances in two major types of technologies allowed great advances in the discovery of new genomic anomalies causing intellectual disability: array comparative genomic hybridization and massive parallel sequencing. Array comparative genomic hybridization allowed a high resolution genome wide investigation of copy number variations leading to the discovery of many novel microdeletion/microduplication syndromes. Massive parallel sequencing evolved in a way that the sequencing of all the genome (or, at a lower cost, all the exons) is now possible to perform in any genetic laboratory in a time and cost-efficient manner, allowing the discovery of many novel variants in previously known and newly discovered intellectual disability genes. These two approaches have provided significantly new insights into the biological pathways associated with intellectual disability and tremendously improved the diagnostic process. In this study we applied these two technologies to the study of the genetic basis of neurodevelopmental disorders. We studied a big group of patients with idiopathic intellectual disability by aCGH (which included two cohorts with different selection criteria - a research and a clinical cohort), a group of patients with a Rett syndrome-like clinical presentation by exome sequencing and re-analyzed exome data from a pediatric heterogeneous cohort. Array comparative genomic hybridization allowed the detection of previously known microdeletion and microduplication syndromes in patients with until then unexplained intellectual disability, with yields of 13% in the research cohort and 18% in the clinical cohort. Importantly it also allowed the discovery of 12 new loci likely to cause neurodevelopmental disease as well as the gathering of additional patients with overlapping genomic imbalances and phenotypic features, allowing the definition of new (rare) syndromes. Massive parallel sequencing – more specifically whole exome sequencing - was applied to a group of patients sharing similar clinical presentation (Rett syndrome-like) and proved to be very effective, leading to the identification of five new genes possibly involved in intellectual disability (HTT, SMARCA1, GABBR2, RHOBTB2 and EIF4G1). It is currently an accepted fact however, that the data generated by exome sequencing at a certain point in time, may not retrieve the genetic cause of the disease. This limitation is often related with the lack of information regarding the genes detected. Given the always increasing knowledge on genes and pathways involved in neurodevelopmental disorders, the need for reevaluation of older and previously unsolved cases emerges. This strategy was also applied in this work and proven to be extremely useful in the clinical context, adding new patients to help establish the relevance of candidate disease genes and raising new candidate genes (DNAJC21, MYOD1 and PAX7). In summary, this work helped to clarify the genetic basis of disease in several patients until then unsolved, as well as to bring forward new candidate loci and genes for intellectual disability and other neurodevelopmental disorders.
Author: Fátima Lopes
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2884271515