Original articleGenetic and clinical variations in a Norwegian sample diagnosed with Rett syndrome
Introduction
For many years the neurodevelopmental disorder Rett syndrome (RTT, OMIM 312750) has been known as a clinical entity mainly caused by mutations in the MECP2 gene [1]. The disorder almost exclusively affects females, and in its classic form, it is characterized by apparently normal development in the first 6–18 months of life before a regression occurs and acquired skills disappear [2].
The phenotypic spectrum of RTT has evolved since the first description of 22 girls with a homogenous phenotype by Andreas Rett in 1966 [3]. As the number of individuals diagnosed with RTT increased, the phenotypic spectrum widened, and in 1994 the diagnosis included both classic and atypical RTT [4]. The current diagnostic criteria were published in 2010 [2]. In the last decade, the term RTT-like disorders has been used for individuals sharing many clinical characteristics with RTT, but not fulfilling the diagnostic criteria. In contrast to classic and atypical RTT, the term RTT-like disorder is not clearly defined [5].
Also the genotypic spectrum has extended in RTT. In 2004 and 2008, strong associations were found between atypical RTT and mutations in CDKL5 and FOXG1, respectively [6], [7]. In the last decade, next generation sequencing (NGS) has contributed to the identification of mutations in more than 100 genes other than MECP2, CDKL5 and FOXG1 in individuals with RTT or a RTT-like phenotype. Almost half of these were the only identified pathological mutation in individuals fulfilling the diagnostic criteria of classic or atypical RTT [5], [8], [9], [10], [11], [12], [13], [14], [15], [16]. The strong association between MECP2 and RTT is however undisputable, with mutations in MECP2 found in more than 95% of individuals with classic and 70–90% of individuals with atypical RTT [2].
A large number of studies have addressed the genotype in MECP2 negative individuals within the RTT spectrum. There are, however, fewer studies comparing the phenotypes of these individuals to the phenotypes of individuals with MECP2 mutations. Differences in phenotype between individuals with RTT with and without MECP2 mutations have been reported, especially in early development and in epilepsy [17], [18]. In addition, differences between individuals with and without MECP2 mutations have been explored in cohorts not based on RTT phenotypes [19]. With the increased number of genes associated with RTT and the increased number of individuals without RTT with a mutation in MECP2, more knowledge about phenotype-genotype correlations on the genetic level is important for the accuracy in diagnostics.
The present study investigates a population of females diagnosed with RTT through the last three decades. It examines all participants for the phenotypic traits contained in the 2010 diagnostic criteria for RTT, revisits their diagnoses and performs genomic investigations in individuals without an identified causative mutation. In addition, the study compares the phenotypes of individuals with and without a MECP2 mutation in the entire RTT group as well as within the RTT diagnostic subgroups of classic and atypical RTT.
Section snippets
Participants
Recruitment took place from 2013 to 2017. Invitation to participate was distributed to families or guardians of females with RTT or a RTT-like disorder through the Norwegian Rett Syndrome Association (n = 126) and Frambu, the Norwegian Resource Centre for Rare Disorders (n = 116). The rate of overlapping between the two search groups was high, as only 165 subjects with RTT had been reported to the Norwegian Patient Registry from the Specialist Health Services in 2013. Lists of names from these
Results
Consent to participate was given on behalf of 93 individuals. Two were excluded due to missing clinical or genetic data, leaving 91 individuals available for analyses. The participants were from 1 to 66 years old, with a median age of 19 (interquartile range 8–30). All geographical parts of Norway were represented, and both rural and urban areas. Half of the participants (53%) lived in the parental home and half (47%) in residential facilities.
Discussion
In this cohort with presumed RTT, the use of Next Generation Sequencing to supplement the targeted approach enabled the identification of mutations in six different genes as well as a copy number variant. The genetic heterogeneity in this cohort is in line with other studies [25], [26], [27]. The clinical diagnosis of RTT was confirmed in 92% of study participants. The finding of a presumed pathogenic mutation in MECP2 in 88% of individuals with confirmed RTT is in agreement with current
Acknowledgements
First and foremost we will like to thank all participants and their families. In addition, we will thank the Norwegian Rett Syndrome Association for support and advices, Frambu Resource Centre for Rare Disorders and habilitation centres in Norway for their support, Lene Hjertnes for help with the interpretation of genetic findings.
Funding
MWH is funded by Vestre Viken Hospital Trust and HB by Innlandet Hospital Trust. The funders have not had any role in the design of the study, data collection, analyses, interpretation of data, or in writing of the article.
Declarations of interest
The authors declare no conflict of interest.
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2021, International Journal of Molecular Sciences