Current developments in the genetics of Rett and Rett-like syndrome

Ehrhart, Friederike; Sangani, Nasim Bahram; Curfs, Leopold

doi:10.1097/yco.0000000000000389

Cited by 41 publications

(58 citation statements)

References 43 publications

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“…Most of the de novo mutations occur almost exclusively in the paternal gamete (Trappe et al, ). Currently, about 800 different mutations of MECP2 gene causing RTT have been identified: point mutations, insertions, duplications, small or large deletions in almost all parts of the gene (Ehrhart et al, ). Majority of causative mutations has been found in eight single‐nucleotide polymorphism hotspots as missense and nonsense mutations: T158M; R255X; R168X; R306C; R294X; R270X; R133C (Kyle et al, ; Percy et al, ).…”

Section: Current Update In the Genetic Of Rett Syndromementioning

confidence: 99%

“…Despite this, phenotype variations commonly occur between patients with the same mutation. Some possible explanation has been proposed, as differences in X chromosome inactivation (Ehrhart et al, ; Knudsen et al, ) and the presence of a second gene mutation, acting as modifier, alleviating or enhancing the phenotype outcome (Zeev et al, ).…”

Section: Current Update In the Genetic Of Rett Syndromementioning

confidence: 99%

“…In the last few years, using whole exome sequencing, many other uncommon genetic mutations in 69 new genes have been identified as causative for RTT phenotype (classic or variant) (Ehrhart et al, ; Table ).…”

Section: Current Update In the Genetic Of Rett Syndromementioning

confidence: 99%

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Epilepsy and genetic in Rett syndrome: A review

et al. 2019

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Introduction Rett syndrome (RTT) is a severe X‐linked neurodevelopmental disorder that primarily affects girls, with an incidence of 1:10,000–20,000. The diagnosis is based on clinical features: an initial period of apparently normal development (ages 6–12 months) followed by a rapid decline with regression of acquired motor skills, loss of spoken language and purposeful hand use, onset of hand stereotypes, abnormal gait, and growth failure. The course of the disease, in its classical form, is characterized by four stages. Three different atypical variants of the disease have been defined. Epilepsy has been reported in 60%–80% of patients with RTT; it differs among the various phenotypes and genotypes and its severity is an important contributor to the clinical severity of the disease. Methods In this manuscript we reviewed literature on RTT, focusing on the different genetic entities, the correlation genotype–phenotype, and the peculiar epileptic phenotype associated to each of them. Results Mutations in MECP2 gene, located on Xq28, account for 95% of typical RTT cases and 73.2% of atypical RTT. CDKL5 and FOXG1 are other genes identified as causative genes in atypical forms of RTT. In the last few years, a lot of new genes have been identified as causative genes for RTT phenotype. Conclusions Recognizing clinical and EEG patterns in different RTT variants may be useful in diagnosis and management of these patients.

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Section: Current Update In the Genetic Of Rett Syndromementioning

confidence: 99%

Section: Current Update In the Genetic Of Rett Syndromementioning

confidence: 99%

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Epilepsy and genetic in Rett syndrome: A review

et al. 2019

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“…The recent advent of Next Generation Sequencing (NGS) technologies allowed discovering many genes involved in these conditions. The study of undiagnosed cases with similar clinical manifestations through whole exome or genome sequencing highlighted the wide spectrum of phenotypic expression of some well-known genetic conditions, such as Rett syndrome, that can be caused by different genes involved in common biological pathways (Ehrhart et al, 2018). We are moving from a phenotypic-based to a genecentered view of the diseases and we are incorporating the concept of disease network in the classification of the genetic conditions (Barabási et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Intellectual disability and Autism comorbidity through gene panel sequencing

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Bellini

Gasparini

et al. 2019

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Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next generation sequencing (NGS) gene panel that has been transferred into clinical practice, replacing single disease gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%.Our data also support the pathogenic role of genes recently proposed to be involved in ASD.Although many of the identified variants need further investigation to be considered diseasecausing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

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“…With the increasing use of next-generation sequencing (NGS) for investigating MECP2 mutation-negative patients with RTT-like phenotypes, pathogenic variants in recognized as well as novel genes have been reported (Lopes et al, 2016;Lucariello et al, 2016). To date, at least 29 OMIM genes have been associated with RTT-like phenotypes (Ehrhart, Sangani, & Curfs, 2018;Percy et al, 2018;Schönewolf-Greulich et al, 2017). Some, are related to early epileptic encephalopathies including STXBP1, SCN1A, SCN2A, SCN8A, GRIN2A, GRIN2B, SLC6A1, KCNA2, and KCNB1 (Allou et al, 2017;Baasch et al, 2014;Cogliati et al, 2019;Olson et al, 2015;Romaniello et al, 2015;Schönewolf-Greulich et al, 2017).…”

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confidence: 99%

Netrin‐G2 dysfunction causes a Rett‐like phenotype with areflexia

et al. 2019

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We describe the underlying genetic cause of a novel Rett-like phenotype accompanied by areflexia in three methyl-CpG-binding protein 2-negative individuals from two unrelated families. Discovery analysis was performed using whole-exome sequencing followed by Sanger sequencing for validation and segregation. Functional studies using short-hairpin RNA for targeted gene knockdown were implemented by the transfection of mouse cultured primary hippocampal neurons and in vivo by in utero electroporation. All patients shared a common homozygous frameshift mutation (chr9:135073515, c.376dupT, p.(Ser126PhefsTer241)) in netrin-G2 (NTNG2, NM_032536.3) with predicted nonsensemediated decay. The mutation fully segregated with the disease in both families. The knockdown of either NTNG2 or the related netrin-G family member NTNG1 resulted in severe neurodevelopmental defects of neuronal morphology and migration. While NTNG1 has previously been linked to a Rett syndrome (RTT)-like phenotype, this is the first description of a RTT-like phenotype caused by NTNG2 mutation. Netrin-G proteins have been shown to be required for proper axonal guidance during early brain development and involved in N-methyl-D-aspartate-mediated synaptic transmission. Our results demonstrating that knockdown of murine NTNG2 causes severe impairments of neuronal morphology and cortical migration are consistent with those of RTT animal models and the shared

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Current developments in the genetics of Rett and Rett-like syndrome

Abstract: We conclude that the Rett syndrome phenotype has a much broader underlying genetic cause and the typical phenotype overlap with other genetic disorders. For proper genetic counselling, patient perspective and treatment it is important to include both phenotype and genetic information.

Cited by 41 publications

References 43 publications

Epilepsy and genetic in Rett syndrome: A review

Epilepsy and genetic in Rett syndrome: A review

Characterization of Intellectual disability and Autism comorbidity through gene panel sequencing

Netrin‐G2 dysfunction causes a Rett‐like phenotype with areflexia

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