Research Centre for Medical Genetics
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Moscow 115522, Russian Federation
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RCMG Identified New Genetic Causes of Intellectual Disabilities and Proposed the Most Effective Way to Diagnose Them

The specialists of the genome editing laboratory of the Research Centre for Medical Genetics identified 25 new, previously unspecified variants in genes related to intellectual disabilities. More than 90% of the detected mutations occurred in patients de novo, that is, appeared spontaneously and were not inherited from parents. It was also possible to propose the most optimal method to identify the genetic causes of intellectual disabiliries - a combination of chromosome micro-matrix analysis and mass parallel sequencing of exome (NGS, MPC).

The study was carried out within the framework of the state assignment of the Ministry of Science and Higher Education of the Russian Federation. The article devoted to the study was published in «International Journal of Molecular Sciences» (IF 6.2, Q1).

Today, it is known that 25 to 50% of cases of intellectual disabilities are the result of anomalies at the chromosome or gene level. Therefore, interest in studying the genetic causes of these pathologies has been growing rapidly in recent years.

The international medical databases of OMIM, HGMD and the scientific literature now contain information on more than 1,700 genes, mutations in which lead to monogenic diseases that are symptomatic of mental retardation. This list is constantly being expanded by the description of new forms. In this case, pathogenic variants of the same gene can lead to both syndromic mental retardation and non-specific intellectual disability.

The high-throughput technologies such as MPC and chromosomal micro-matrix analysis have enabled clinical practice not only to effectively diagnose selected genetic variants of syndromic and non-syndromic forms of intellectual disability, but also to identify the new genes responsible for their origin.

To conduct the research the experts from the genome editing laboratory at RCMG selected 198 patients with non-specific intellectual disabilities from 171 families. The age ranged from 6 months to 65 years. These patients were unable to diagnose with standard methods of analysis, such as karyotype or individual genes research. Therefore, RCMG specialists applied a combination of two most modern methods - exome sequencing and chromosomal micro-matrix analysis. This proved to be the most effective method of diagnostics and revealed 46 mutations in the genes associated with intellectual disabilities, 25 of which had not been previously described, and 16 chromosomal microstructural realignments.

«We identified three variants in two genes associated with Coffin-Siris syndrome (SMARCA4, SOX4 ), two variants in the ADNP gene (Helsmoortel-Van der Aa syndrome), one variant in the SMARCA2 gene (Nicolaides-Baraitser syndrome) and one variant in the ACTL6B gene. All of them are related to the BAF complex (SWI/SNF),» - explained Olga Levchenko, the researcher of genome editing laboratory.

 It is noteworthy that the patients involved in the study did not have specific manifestations of any of these syndromes, and the doctors couldn’t offer targeted genetic analysis. Our results demonstrate that the combination of MPC and chromosomal micro-matrix analysis allows to determine the cause of the disease in a significant portion of cases. We were able to establish a molecular-genetic diagnosis for 61 patients, so the diagnostic efficiency was 35.7%, which is higher than that of many foreign researchers.

The laboratory specialists also described the phenotypes of patients in details, which should help other laboratories to improve the efficiency of diagnostics. All newly detected mutations will be entered into the international ClinVar database.