Microdeletions Including FMR1 in Three Female Patients with Intellectual Disability - Further Delineation of the Phenotype and Expression Studies

Zink, Alexander M.; Wohlleber, Eva; Engels, Hartmut; Rødningen, Olaug K.; Ravn, Kirstine; Heilmann, Stefanie; Rehnitz, Julia; Katzorke, N.; Kraus, Cornelia; Blichfeldt, Susanne; Hoffmann, Per; Reutter, Heiko; Brockschmidt, Felix F.; Kreiß-Nachtsheim, Martina; Vogt, Peter H.; Prescott, Trine; Tümer, Zeynep; Lee, J.A.

doi:10.1159/000357962

Cited by 6 publications

(5 citation statements)

References 23 publications

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“…To date, only 10 female index patients with deletions harboring FMR1 have been reported. Moreover, the severity of the phenotype for females with FMR1 deletions correlates with their X-chromosome inactivation [23] – [25] .…”

Section: Discussionmentioning

confidence: 99%

Screening for Intellectual Disability Using High-Resolution CMA Technology in a Retrospective Cohort from Central Brazil

et al. 2014

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Intellectual disability is a complex, variable, and heterogeneous disorder, representing a disabling condition diagnosed worldwide, and the etiologies are multiple and highly heterogeneous. Microscopic chromosomal abnormalities and well-characterized genetic conditions are the most common causes of intellectual disability. Chromosomal Microarray Analysis analyses have made it possible to identify putatively pathogenic copy number variation that could explain the molecular etiology of intellectual disability. The aim of the current study was to identify possible submicroscopic genomic alterations using a high-density chromosomal microarray in a retrospective cohort of patients with otherwise undiagnosable intellectual disabilities referred by doctors from the public health system in Central Brazil. The CytoScan HD technology was used to detect changes in the genome copy number variation of patients who had intellectual disability and a normal karyotype. The analysis detected 18 CNVs in 60% of patients. Pathogenic CNVs represented about 22%, so it was possible to propose the etiology of intellectual disability for these patients. Likely pathogenic and unknown clinical significance CNVs represented 28% and 50%, respectively. Inherited and de novo CNVs were equally distributed. We report the nature of CNVs in patients from Central Brazil, representing a population not yet screened by microarray technologies.

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Section: Discussionmentioning

confidence: 99%

Screening for Intellectual Disability Using High-Resolution CMA Technology in a Retrospective Cohort from Central Brazil

et al. 2014

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“…It also predicts that in a subset of patients, an inactivation of the same gene could happen due to a missense, indel, or frameshift mutation, instead of repeat expansion. Both of these predictions are true for autosomal recessive FRDA (62), progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) (63), Congenital insensitivity to pain (44), X-linked Duchenne muscular dystrophy (64), and fragile X syndrome (65,66).…”

Section: From Expanded Dna Repeats To Diseasementioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

216

239

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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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“…Female patients, harboring the Xq27.3q28 deletions, present a variety of clinical features. We summarize the clinical features, deleted regions in Xq27q28, and XCI states (random/skewed/selected) of the two presented patients, along with ten female and three male patients in Figure 6 and Table 1 (Birot et al, 1996;Brusius-Facchin et al, 2012;Burruss, Wood, Espinoza, Dwivedi, & Holden, 2012;Clarke et al, 1991Clarke et al, , 1992Clarke, Willard, Teshima, Chang, & Skomorowski, 1990;Dahl et al, 1995;Marshall et al, 2013;Probst et al, 2007;Schmidt et al, 1990Schmidt et al, , 1992Zink et al, 2014). All patients had FMR1, AFF2, and IDS deletions on one allele.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular genetic characterization of two female patients harboring the Xq27.3q28 deletion with different ratios of X chromosome inactivation

et al. 2020

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A heterozygous deletion at Xq27.3q28 including FMR1, AFF2, and IDS causing intellectual disability and characteristic facial features is very rare in females, with only 10 patients having been reported. Here, we examined two female patients with different clinical features harboring the Xq27.3q28 deletion and determined the chromosomal breakpoints. Moreover, we assessed the X chromosome inactivation (XCI) in peripheral blood from both patients. Both patients had an almost overlapping deletion at Xq27.3q28, however, the more severe patient (Patient 1) showed skewed XCI of the normal X chromosome (79:21) whereas the milder patient (Patient 2) showed random XCI. Therefore, deletion at Xq27.3q28 critically affected brain development, and the ratio of XCI of the normal X chromosome greatly affected the clinical characteristics of patients with deletion at Xq27.3q28. As the chromosomal breakpoints were determined, we analyzed a change in chromatin domains termed topologically associated domains (TADs) using published Hi‐C data on the Xq27.3q28 region, and found that only patient 1 had a possibility of a drastic change in TADs. The altered chromatin topologies on the Xq27.3q28 region might affect the clinical features of patient 1 by changing the expression of genes just outside the deletion and/or the XCI establishment during embryogenesis resulting in skewed XCI.

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Microdeletions Including FMR1 in Three Female Patients with Intellectual Disability - Further Delineation of the Phenotype and Expression Studies

Cited by 6 publications

References 23 publications

Screening for Intellectual Disability Using High-Resolution CMA Technology in a Retrospective Cohort from Central Brazil

Screening for Intellectual Disability Using High-Resolution CMA Technology in a Retrospective Cohort from Central Brazil

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Clinical and molecular genetic characterization of two female patients harboring the Xq27.3q28 deletion with different ratios of X chromosome inactivation

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