Utility of Next Generation Sequencing for Molecular Diagnostics in Rett Syndrom - Nursing Assignment Help

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Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that almost exclusively afects girls and is totally disabling. Three genes have been identifed that cause RTT: MECP2, CDKL5 and FOXG1. However, the etiology of some of RTT patients still remains unknown. Recently, next generation sequencing (NGS) has promoted genetic diagnoses because of the quickness and afordability of the method. To evaluate the usefulness of NGS in genetic diagnosis, we present the genetic study of RTTlike patients using diferent techniques based on this technology. We studied 1577 patients with RTTlike clinical diagnoses and reviewed patients who were previously studied and thought to have RTT genes by Sanger sequencing. Genetically, 477 of 1577 patients with a RTT-like suspicion have been diagnosed. Positive results were found in 30% by Sanger sequencing, 23% with a custom panel, 24% with a commercial panel and 32% with whole exome sequencing. A genetic study using NGS allows the study of a larger number of genes associated with RTT-like symptoms simultaneously, providing genetic study of a wider group of patients as well as signifcantly reducing the response time and cost of the study. Rett syndrome (RTT; MIM# 312750) is a neurodevelopmental disorder of early onset that afects girls almost exclusively. RTT was originally described in the 1960s by Andreas Rett1 . Tis syndrome is frst recognized in infancy with a period of apparently normal development (up to the age of 6–18 months), followed by a regression characterized by loss of speech and purposeful hand use and motor apraxia that may be associated with epilepsy and dysautonomic features, including disturbed breathing, sleep and gastrointestinal motility1,2 . RTT has an incidence of 1:10,000 live female births and is the second cause of intellectual disability afer Down’s syndrome in females3 . RTT was clinically cataloged into classic and atypical forms of the disease. However, these criteria have undergone several updates over the past three decades.

Consensus criteria have been established that distinguish RTT patients into the individual classifcations of classic or typical RTT and the atypical or variant forms of RTT4–6 . A large number of reports support the evidence that mutations in the Methyl CpG binding protein 2 gene (MECP2; MIM *300005) are the major causes of classical RTT7,8 . Over 95% of the cases are explained by more than 800 reported mutations in the methyl CpG-binding protein 2 gene (MECP2) (RettBASE: MECP2 Variation Database)9,10. MeCP2 is a transcriptional regulatory protein, and in its absence, a large number of genes exhibit abnormal expression with implications in the balance between synaptic excitation and inhibition11. Although the majority of RTT patients have mutations in the MECP2 gene10, approximately 5% of classical RTT and 25% of variant RTT patients are negative for MECP2 mutation6,12. In this variant RTT group of patients, some have mutations in other genes that are also associated with RTT: cyclin-dependent kinase-like5 (CDKL5; MIM *300203), which is described in individuals with an early seizure onset variant of RTT13, and Forkhead box protein G1 (FOXG1; MIM *164874), which is responsible for the congenital variant of RTT14. In addition, with 1Molecular and Genetics Medicine Section, Hospital Sant Joan de Déu, Barcelona, Spain. 2Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain. 3Centro Nacional de Análisis Genómica (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. 4 Neurology Service, Hospital Sant Joan de Déu, Barcelona, Spain. 5 Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona, Spain. 6CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III, Madrid, Spain. *A comprehensive list of consortium members appears at the end of the paper. Correspondence and requests for materials should be addressed to J.A

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