{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:19:07Z","timestamp":1790813947823,"version":"4.1.0"},"reference-count":128,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T00:00:00Z","timestamp":1632614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI15\/01159"],"award-info":[{"award-number":["PI15\/01159"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI20\/00389"],"award-info":[{"award-number":["PI20\/00389"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FPU (Formaci\u00f3n del Profesorado Universitario) doctoral grant from the Spanish Ministry of Science, Innovation and Universities","award":["FPU18\/02152"],"award-info":[{"award-number":["FPU18\/02152"]}]},{"name":"Mu\u00e9vete por los que no Pueden","award":["PCP\/00282"],"award-info":[{"award-number":["PCP\/00282"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rett syndrome (RTT) is a severe neurodevelopmental disorder that constitutes the second most common cause of intellectual disability in females worldwide. In the past few years, the advancements in genetic diagnosis brought by next generation sequencing (NGS), have made it possible to identify more than 90 causative genes for RTT and significantly overlapping phenotypes (RTT spectrum disorders). Therefore, the clinical entity known as RTT is evolving towards a spectrum of overlapping phenotypes with great genetic heterogeneity. Hence, simultaneous multiple gene testing and thorough phenotypic characterization are mandatory to achieve a fast and accurate genetic diagnosis. In this review, we revise the evolution of the diagnostic process of RTT spectrum disorders in the past decades, and we discuss the effectiveness of state-of-the-art genetic testing options, such as clinical exome sequencing and whole exome sequencing. Moreover, we introduce recent technological advancements that will very soon contribute to the increase in diagnostic yield in patients with RTT spectrum disorders. Techniques such as whole genome sequencing, integration of data from several \u201comics\u201d, and mosaicism assessment will provide the tools for the detection and interpretation of genomic variants that will not only increase the diagnostic yield but also widen knowledge about the pathophysiology of these disorders.<\/jats:p>","DOI":"10.3390\/ijms221910375","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T04:55:33Z","timestamp":1632718533000},"page":"10375","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Technological Improvements in the Genetic Diagnosis of Rett Syndrome Spectrum Disorders"],"prefix":"10.3390","volume":"22","author":[{"given":"Clara","family":"Xiol","sequence":"first","affiliation":[{"name":"Fundaci\u00f3 per la Recerca Sant Joan de D\u00e9u, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain"},{"name":"Institut de Recerca Sant Joan de D\u00e9u, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Heredia","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3 per la Recerca Sant Joan de D\u00e9u, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain"},{"name":"Institut de Recerca Sant Joan de D\u00e9u, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainhoa","family":"Pascual-Alonso","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3 per la Recerca Sant Joan de D\u00e9u, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain"},{"name":"Institut de Recerca Sant Joan de D\u00e9u, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Oyarzabal","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3 per la Recerca Sant Joan de D\u00e9u, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain"},{"name":"Institut de Recerca Sant Joan de D\u00e9u, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain"},{"name":"CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Institut de Recerca Sant Joan de D\u00e9u, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain"},{"name":"CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Clinical Genetics, Molecular and Genetic Medicine Section, Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nrneurol.2016.186","article-title":"Clinical and biological progress over 50 years in Rett syndrome","volume":"13","author":"Leonard","year":"2016","journal-title":"Nat. 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