Distribution of autosomal fragile sites in specimens cultured for prenatal fragile X diagnosis

Krawczun, Michael S.; Jenkins, Edmund C.; Duncan, Charlotte J.; Stark‐Houck, Sandra L.; Kunaporn, Suphat; Schwartz-Richstein, Carol; Gu, Hong; Brown, W. Ted

doi:10.1002/ajmg.1320380264

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…It is interesting to note that the deletion of 16q23.1 overlaps one of the most frequently observed common fragile sites (FRA16D) [Krawczun et al, 1991; Smith et al, 1998; Lukusa and Fryns, 2008]. Common fragile sites have been implicated in genome instability as potential hotspots for chromosomal deletions and translocations [Lukusa and Fryns, 2008].…”

Section: Discussionmentioning

confidence: 99%

De novo and complex imbalanced chromosomal rearrangements revealed by array CGH in a patient with an abnormal phenotype and apparently “balanced” paracentric inversion of 14(q21q23)

Jiang

Martínez

et al. 2008

American J of Med Genetics Pt A

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Paracentric inversions are one of the common chromosomal rearrangements typically associated with a normal phenotype. However, if dosage-sensitive genes are disrupted by the breakpoints, an abnormal phenotype could result. Detection of paracentric inversions often relies on careful high resolution banding, which has limited sensitivity. We report here cytogenetic studies performed on a 4-year-old female patient with global developmental delay, hypotonia, and dysmorphic features. The initial cytogenetic evaluation by G-banding revealed a de novo inversion of chromosome 14. Subsequent array CGH analysis using both a targeted BAC array and a high-resolution oligonucleotide array revealed microdeletions at the breakpoints of 14q21.1 (0.8 Mb) and 14q23.1 (0.9 Mb). Unexpectedly, a microdeletion in the region of 16q23.1 (1.3 Mb) was also identified, which overlaps with the common fragile site FRA16D. Parental chromosome and FISH analyses were normal, supporting the conclusion that these microdeletions were de novo in the patient and likely contributed to her abnormal phenotype. The case report presented illustrates the value of using high-resolution microarray analysis for phenotypically abnormal individuals with apparently balanced chromosomal rearrangements, including inversions.

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Section: Discussionmentioning

confidence: 99%

De novo and complex imbalanced chromosomal rearrangements revealed by array CGH in a patient with an abnormal phenotype and apparently “balanced” paracentric inversion of 14(q21q23)

Jiang

Martínez

et al. 2008

American J of Med Genetics Pt A

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“…All the currently identified RFSs, which have been cytogenetically defined and mapped and many cloned and sequenced, are highlighted in Table 2 , along with known features and disease links for each. Numerous attempts to identify internal controls for diagnostic FXS by FRAXA induction revealed many sites that presented low-level (<4%) folate-sensitive fragility (reviewed in ( Krawczun et al, 1991 ). In the proper population (disease or other) and induction systems, new rare fragile sits may be discovered.…”

Section: Introductionmentioning

confidence: 99%

“… Size ranges of repeats for some of the mapped fragile sites are reported estimates, which in some cases are limited by the small number of affected and reported families. Other fragile sites that presented low-level (<4%) folate-sensitive fragility have been documented are covered in detail elsewhere ( Krawczun et al, 1991 ). …”

Section: Introductionmentioning

confidence: 99%

Fragile sites, chromosomal lesions, tandem repeats, and disease

Mirceta

Shum²,

Schmidt³

et al. 2022

Front. Genet.

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Expanded tandem repeat DNAs are associated with various unusual chromosomal lesions, despiralizations, multi-branched inter-chromosomal associations, and fragile sites. Fragile sites cytogenetically manifest as localized gaps or discontinuities in chromosome structure and are an important genetic, biological, and health-related phenomena. Common fragile sites (∼230), present in most individuals, are induced by aphidicolin and can be associated with cancer; of the 27 molecularly-mapped common sites, none are associated with a particular DNA sequence motif. Rare fragile sites (≳ 40 known), ≤ 5% of the population (may be as few as a single individual), can be associated with neurodevelopmental disease. All 10 molecularly-mapped folate-sensitive fragile sites, the largest category of rare fragile sites, are caused by gene-specific CGG/CCG tandem repeat expansions that are aberrantly CpG methylated and include FRAXA, FRAXE, FRAXF, FRA2A, FRA7A, FRA10A, FRA11A, FRA11B, FRA12A, and FRA16A. The minisatellite-associated rare fragile sites, FRA10B, FRA16B, can be induced by AT-rich DNA-ligands or nucleotide analogs. Despiralized lesions and multi-branched inter-chromosomal associations at the heterochromatic satellite repeats of chromosomes 1, 9, 16 are inducible by de-methylating agents like 5-azadeoxycytidine and can spontaneously arise in patients with ICF syndrome (Immunodeficiency Centromeric instability and Facial anomalies) with mutations in genes regulating DNA methylation. ICF individuals have hypomethylated satellites I-III, alpha-satellites, and subtelomeric repeats. Ribosomal repeats and subtelomeric D4Z4 megasatellites/macrosatellites, are associated with chromosome location, fragility, and disease. Telomere repeats can also assume fragile sites. Dietary deficiencies of folate or vitamin B12, or drug insults are associated with megaloblastic and/or pernicious anemia, that display chromosomes with fragile sites. The recent discovery of many new tandem repeat expansion loci, with varied repeat motifs, where motif lengths can range from mono-nucleotides to megabase units, could be the molecular cause of new fragile sites, or other chromosomal lesions. This review focuses on repeat-associated fragility, covering their induction, cytogenetics, epigenetics, cell type specificity, genetic instability (repeat instability, micronuclei, deletions/rearrangements, and sister chromatid exchange), unusual heritability, disease association, and penetrance. Understanding tandem repeat-associated chromosomal fragile sites provides insight to chromosome structure, genome packaging, genetic instability, and disease.

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Bibliography on X‐linked mental retardation, the fragile X, and related subjects V (1991)

Spano

Opitz

1991

Am. J. Med. Genet.

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Distribution of autosomal fragile sites in specimens cultured for prenatal fragile X diagnosis

Cited by 5 publications

References 25 publications

De novo and complex imbalanced chromosomal rearrangements revealed by array CGH in a patient with an abnormal phenotype and apparently “balanced” paracentric inversion of 14(q21q23)

De novo and complex imbalanced chromosomal rearrangements revealed by array CGH in a patient with an abnormal phenotype and apparently “balanced” paracentric inversion of 14(q21q23)

Fragile sites, chromosomal lesions, tandem repeats, and disease

Bibliography on X‐linked mental retardation, the fragile X, and related subjects V (1991)

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