Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype

Lucariello, Mario; Vidal, Enrique; Vidal, Silvia M.; Sáez, Mauricio; Roa, Laura M.; Huertas, Dori; Pineda, Merçè; Dalfó, Esther; Dopazo, Joaquín; Jurado, Paola; Armstrong, Judith; Esteller, Manel

doi:10.1007/s00439-016-1721-3

Cited by 65 publications

(87 citation statements)

References 39 publications

(53 reference statements)

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“…In one study of 21 girls with features of RTT, WES was able to identify pathogenic variants in different genes in two-thirds of the cohort. Some of these variants affected genes previously associated with neurodevelopmental phenotypes, such as HCN1 , SCN1A , TCF4 , GRIN2B , SLC6A1 , while others were in candidate genes not previously associated with neurodevelopmental disorders, such as SEMA6B [7]. In another study of 22 patients with RTT, who had prior negative clinical testing for mutations in MECP2 , CDKL5 , and FOXG1 , WES revealed likely pathogenic variants in the majority of cases, including in IQSEC2 , TCF4 , and WDR45 [10], three of the genes identified in our cohort.…”

Section: Discussionmentioning

confidence: 99%

“…In one study that evaluated 21 females with features of RTT, two-thirds of the patients had pathogenic variants in genes other than MECP2 , CDKL5 , and FOXG1 [7]. In another study of 19 patients with features of RTT, two had pathogenic genomic imbalances, six had variants in genes already associated with neurodevelopmental disorders, and five had variants in candidate disease genes [8].…”

Section: Introductionmentioning

confidence: 99%

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Monogenic disorders that mimic the phenotype of Rett syndrome

et al. 2018

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Background. Rett syndrome (RTT) is caused by mutations in methyl-CpG binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. Methods. We performed a retrospective chart review on n=319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results (3) ultimately arrived at a diagnosis other than RTT with WES. Results. n=7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These 7 patients collectively possessed pathogenic variants in 6 different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n=2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT associated features included the following: loss of hand or language skills (n=3; IQSEC2, KCNB1 × 2); disrupted sleep (n=4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n=5; FOXG1, KNCB1 × 2, MEIS2, TCF4); bruxism (n=3; KCNB1 × 2; TCF4); and hypotonia (n=7). Conclusion. Clinically-based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Monogenic disorders that mimic the phenotype of Rett syndrome

et al. 2018

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“…Fetal pads on fingers and toes, and stereotypic hand movements such as hand clapping are important features. TCF4 is the main causative gene for the classical Pitt‐Hopkins phenotype; variants in this gene have also been reported in 2 patients with a Rett‐like phenotype . In the Danish cohort, a single patient suspected of having RTT due to hyperventilation and hand stereotypies has a pathogenic TCF4 variant (Table ).…”

Section: Clinical or Genetic Diagnosis?mentioning

confidence: 99%

“…The most common genes involved apart from MECP2 are: CDKL5 (cyclin‐dependent kinase‐like 5), in which variants cause the early onset seizure disorder and FOXG1 , which is responsible for the congenital RTT variant . Several additional new genes have been suggested to be associated with atypical RTT and a Rett‐like disorder . These studies have also revealed previously unrecognized clinical similarities of Rett spectrum phenotypes with other neurodevelopmental disorders.…”

Section: Introductionmentioning

confidence: 99%

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

et al. 2018

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The differential diagnostics in Rett syndrome has evolved with the development of next generation sequencing-based techniques and many patients have been diagnosed with other syndromes or variants in newly described genes where the associated phenotype(s) is yet to be fully explored. The term Rett-like refers to phenotypes with distinct overlapping features of Rett syndrome where the clinical criteria are not completely fulfilled. In this study we have combined a review of Rett-like disorders with data from a Danish cohort of 35 patients with Rett-like phenotypes emphasizing the diagnostic overlap with Pitt-Hopkins syndrome, Cornelia de Lange syndrome with SMC1A variants, and epileptic encephalopathies, for example, due to STXBP1 variants. We also found a patient with a pathogenic variant in KCNB1, which has not been previously linked to a Rett-like phenotype. This study underlines the clinical and genetic heterogeneity of a Rett syndrome spectrum, and provides an overview of the Rett syndrome-related genes described to date, and hence serves as a guide for diagnosing patients with Rett-like phenotypes.

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“…Rarely, mutations in CDKL5 , SHANK3 , FOXG1 , ANKRD31 , and CHRNA5 cause a RTT-like phenotype [8–10]. …”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress

et al. 2017

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BackgroundRett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for the gene expression and chromatin regulator, methyl-CpG binding protein 2. Although the behavioral phenotype appears to be primarily due to neuronal Mecp2 deficiency in mice, other cell types, including astrocytes and oligodendrocytes, also appear to contribute to some aspects of the RTT phenotype. In addition, microglia may also play a role. However, the effect of Mecp2 deficiency in microglia on RTT pathogenesis is controversial.MethodsIn the current study, we applied whole transcriptome analysis using RNA-seq to gain insight into molecular pathways in microglia that might be dysregulated during the transition, in female mice heterozygous for an Mecp2-null allele (Mecp2 +/−; Het), from the pre-phenotypic (5 weeks) to the phenotypic phases (24 weeks).ResultsWe found a significant overlap in differentially expressed genes (DEGs) with genes involved in regulating the extracellular matrix, and those that are activated or inhibited when macrophages and microglia are stimulated towards the M1 and M2 activation states. However, the M1- and M2-associated genes were different in the 5- and 24-week samples. In addition, a substantial decrease in the expression of nine members of the heat shock protein (HSP) family was found in the 5-week samples, but not at 24 weeks.ConclusionsThese findings suggest that microglia from pre-phenotypic and phenotypic female mice are activated in a manner different from controls and that pre-phenotypic female mice may have alterations in their capacity to response to heat stress and other stressors that function through the HSP pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0134-z) contains supplementary material, which is available to authorized users.

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Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype

Cited by 65 publications

References 39 publications

Monogenic disorders that mimic the phenotype of Rett syndrome

Monogenic disorders that mimic the phenotype of Rett syndrome

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress

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