Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location

Cheadle, Jeremy P.; Gill, Harinder; Fleming, Nick; Maynard, Julie; Kerr, Alison; Leonard, Helen; Krawczak, Michael; Cooper, David Neil; Lynch, Sally Ann; Thomas, Nicholas Stuart Tudor; Hughes, Helen E.; Hultén, Maj; Ravine, David; Sampson, Julian R.; Clarke, Angus

doi:10.1093/hmg/9.7.1119

Cited by 251 publications

(233 citation statements)

References 29 publications

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“…However, when comparing the clinical features of patients with a CHD7 missense mutation with patients with a truncating mutation, we have shown that missense mutations are, in general, associated with a milder phenotype (Table 4). This association is also seen in other syndromes, for example, Rett syndrome [Cheadle et al, 2000]. Three features were found significantly more often in the patients with a CHD7 truncating mutation: cleft lip/palate, choanal anomalies, and congenital heart defects.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 59%

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

et al. 2012

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CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo-and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5 and 3 regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations.

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Section: Genotype-phenotype Correlationmentioning

confidence: 59%

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

et al. 2012

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“…So truncating mutations within or downstream of TRD or deletions in the C-terminal region are consistent with reduced clinical severity when compared with truncating mutations N-terminal to this domain. 5 The large fragment deletions are within a hot spot for deletion or insertion. For the mutation 1152del 44 bp, both the donor and acceptor sites of the deletion are ACC.…”

Section: Discussionmentioning

confidence: 99%

MECP2 gene mutation analysis in Chinese patients with Rett syndrome

et al. 2002

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Rett syndrome (RTT) is a progressive neurodevelopmental disorder that affects almost exclusively girls. Mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) have been found to be a cause. In order to study the spectrum of MECP2 mutations in Chinese patients, we employed PCR and sequencing of the coding region of MECP2 gene in 31 Chinese cases of classical sporadic RTT. Mutations in MECP2 were found in about 55%. Twelve different mutations in exon 3 were identified in 17 of these 31 patients; two of these are novel. A novel missense variant was detected in the C-terminal region in a patient and her father who was normal. In addition, there was a single nucleotide variant in the 3'UTR.

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“…The seven most frequently observed and reported MECP2 mutations represent 56.9% (58/102) of all of the identified mutations in our study. Moreover, in some reports, the most common mutation is p. R168X (Cheadle et al 2000;Dragich et al 2000;Wan et al 1999). However, the p. T158M was a predominant finding herein, which is consistent with our previous report (Pan et al 2002) and with reports on cohorts of American (Buyse et al 2000), British-Italian (Vacca et al 2001), Japanese (Fukuda et al 2005), and Korean descent (Chae et al 2002).…”

Section: Cdkl5 Mutation Detection By Dhplc Analysismentioning

confidence: 99%

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome

Pan

Bao

et al. 2006

J Hum Genet

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Rett syndrome (RTT) is a progressive neurodevelopmental disorder that is caused by mutations in the X-linked methyl-CpG-binding protein2 (MECP2) gene. In this study, the MECP2 sequences in 121 unrelated Chinese patients with classical or atypical RTT were screened for deletions and mutations. In all, we identified 45 different MECP2 mutations in 102 of these RTT patients. The p. T158M mutation (15.7%) was the most common, followed in order of frequency by p. R168X (11.8%), p. R133C (6.9%), p. R270X (6.9%), p. G269fs (6.9%), p. R255X (4.9%), and p. R306C (3.9%). In addition, we identified five novel MECP2 mutations: three missense (p. K305E, p. V122M, p. A358T), one insertion (c.45-46ins-GGAGGA), and one 22 bp deletion (c.881-902del22). Large deletions represented 10.5% of all identified MECP2 mutations. Conversely, mutations in exon 1 appeared to be rare (0.9%). The remaining cases without MECP2 mutations were screened for the cyclin-dependent kinase-like 5 (CDKL5) gene using denaturing high-performance liquid chromatography (DHPLC). One synonymous mutation (p. I72I) was found in exon 5, suggesting that CDKL5 is a rare cause of RTT. The overall MECP2 mutation detection rate for this patient series was 84.3:87.9% in 107 classical RTT cases and 57.1% in 14 atypical RTT cases. Moreover, there were two patients with homozygous mutations and normal female karyotypes. However, we did not pinpoint a significant relationship between genotype and phenotype in these cases.

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Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location

Cited by 251 publications

References 29 publications

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

MECP2 gene mutation analysis in Chinese patients with Rett syndrome

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome

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