Additional Clinical and Cytogenetic Findings Associated With Rett Syndrome

Simonic, Ingrid; Gericke, Gerda J.; Lippert, Malcolm J.; Schoeman, Johan

doi:10.1002/(sici)1096-8628(19970531)74:3<331::aid-ajmg16>3.0.co;2-p

Cited by 16 publications

(5 citation statements)

References 17 publications

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“…The first was 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, the second was 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and the third was 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. Simonic et al (1997) observed an increase in the incidence of a breakpoint at Xp22.1 in patients with RTT, which leads us to favor this region. Further support for Xp22 as a candidate region came from the report of a patient with RTT and an (X;3)(p22.11;q13.31) translocation (Zoghbi et al 1990a).…”

Section: X-chromosome Exclusion and Haplotype Mappingmentioning

confidence: 88%

Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation

Weaving

Christodoulou

Williamson

et al. 2004

The American Journal of Human Genetics

441

365

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Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.

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Section: X-chromosome Exclusion and Haplotype Mappingmentioning

confidence: 88%

Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation

Weaving

Christodoulou

Williamson

et al. 2004

The American Journal of Human Genetics

441

365

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“…Furuya et al (1989) described a CFS that accounts for 13.4% of the total BCG scored in human bone marrow cells of healthy persons at 4q21-25 (the most expressed in these cells). Recurrent BCG were also localized at 4q21 or 4q23 in other types of cells (Murano et al, 1989;Caporossi et al, 1995;Gericke et al, 1996;Simonic et al, 1997). In the mouse genome, no CFS was described at 6C1, but one analysis localized a relatively weak site at 6B3, the band directly adjacent to 6C1 (Elder and Robinson, 1989).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

et al. 2004

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Fragile sites are classified as common or rare depending on their occurrence in the populations. While rare sites are mainly associated with inherited diseases, common sites have been involved in somatic rearrangements found in the chromosomes of cancer cells. Here we study a mouse locus containing the ionotropic glutamate receptor delta 2 (grid2) gene in which spontaneous chromosome rearrangements occur frequently, giving rise to mutant animals in inbred populations. We identify and clone common fragile sites overlapping the mouse grid2 gene and its human ortholog GRID2, lying respectively at bands 6C1 and 4q22 in a 7-Mb-long region of synteny. These results show a third example of orthologous common sites conserved at the molecular level, and reveal an unexpected link between an inherited disease and an aphidicolin-sensitive region. Recurrent deletions of subregions of band 4q22 have been previously described in human hepatocellular carcinomas. This 15-Mb-long region appears precisely centered on the site described here, which strongly suggests that it also plays a specific role in hepatic carcinogenesis.

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“…In 1997, Simonic et al published an observation about specific subsets of CFSs in Rett syndrome [38]. In addition, the co-occurrence of trisomy X and de novo pericentromeric inversion on chromosome 2 were found in these reported Rett syndrome patients.…”

Section: Early Observations Of Chromosomal Fragility Observations Con...mentioning

confidence: 99%

A Unifying Hypothesis for the Genome Dynamics Proposed to Underlie Neuropsychiatric Phenotypes

Gericke

2024

Genes

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The sheer number of gene variants and the extent of the observed clinical and molecular heterogeneity recorded in neuropsychiatric disorders (NPDs) could be due to the magnified downstream effects initiated by a smaller group of genomic higher-order alterations in response to endogenous or environmental stress. Chromosomal common fragile sites (CFS) are functionally linked with microRNAs, gene copy number variants (CNVs), sub-microscopic deletions and duplications of DNA, rare single-nucleotide variants (SNVs/SNPs), and small insertions/deletions (indels), as well as chromosomal translocations, gene duplications, altered methylation, microRNA and L1 transposon activity, and 3-D chromosomal topology characteristics. These genomic structural features have been linked with various NPDs in mostly isolated reports and have usually only been viewed as areas harboring potential candidate genes of interest. The suggestion to use a higher level entry point (the ‘fragilome’ and associated features) activated by a central mechanism (‘stress’) for studying NPD genetics has the potential to unify the existing vast number of different observations in this field. This approach may explain the continuum of gene findings distributed between affected and unaffected individuals, the clustering of NPD phenotypes and overlapping comorbidities, the extensive clinical and molecular heterogeneity, and the association with certain other medical disorders.

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Additional Clinical and Cytogenetic Findings Associated With Rett Syndrome

Cited by 16 publications

References 17 publications

Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation

Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

A Unifying Hypothesis for the Genome Dynamics Proposed to Underlie Neuropsychiatric Phenotypes

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