Concurrence of fragile X and Klinefelter syndromes: report of a new case of paternal nondisjunction

Santos, Cíntia Barros; Hjalgrim, Helle; Carneiro, Flavia Raquel Gonçalves; Ribeiro, Márcia Gonçalves; Boy, Raquel; Pimentel, Márcia Mattos Gonçalves

doi:10.1016/s0003-3995(03)00013-3

Cited by 3 publications

(4 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This leads to FMR1 gene silencing and reduced expression of FMRP protein (25), which is the direct cause of the symptoms associated with FXS (26). Furthermore, ChrX aneuploidy has been observed in female carriers (27) and in male FXS patients (28–30), but the mechanism underlying this form of FRAXA instability also remains unknown. It has been speculated that an atypical DNA structure formed by the CGG repeat itself, such as a hairpin-like structure (31), quadruplex (32), or R loop (33, 34), could contribute to its instability.…”

mentioning

confidence: 99%

Folate deficiency drives mitotic missegregation of the human FRAXA locus

Bjerregaard

Garribba

McMurray

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

SignificanceDietary folate deficiency is associated with fetal neural tube defects, psychological disorders, and age-associated dementia. However, it remains unclear how folate deficiency could be a causative factor in such a diverse range of disorders. Through analysis of the FRAXA locus, which contains an extensive CGG repeat sequence, we show that folate deprivation triggers extensive mitotic missegregation of the locus. Moreover, the entire chromosome X becomes unstable during a period of long-term folate deprivation. Considering that the human genome contains several loci associated with extensive CGG repeat regions, these findings suggest a mechanism by which folate deficiency contributes to the onset of a wide range of human diseases.

show abstract

mentioning

confidence: 99%

Folate deficiency drives mitotic missegregation of the human FRAXA locus

Bjerregaard

Garribba

McMurray

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Linkage to COL4A5 detected an extra X chromosome of paternal origin in the proband giving rise to the concurrence of X-linked AS and KS. The 47,XXY karyotype has been identified in males affected by several X-linked diseases such as Fragile X syndrome, 11 Rett syndrome, Increased frequency compared to control group mean (Po0.007).…”

Section: Discussionmentioning

confidence: 99%

Male-to-male transmission of X-linked Alport syndrome in a boy with a 47,XXY karyotype

et al. 2005

View full text Add to dashboard Cite

Alport syndrome (AS) is a genetically heterogeneous renal hereditary disease. Male-to-male transmission has been considered fully indicative of autosomal dominant AS. We report a family with male-to-male transmission of X-linked AS due to an extra X chromosome of paternal origin in the proband. Linkage analysis excluded the autosomal loci and demonstrated segregation with the COL4A5 locus (Xq22.3). Sperm FISH analysis from his father detected an increased XY disomy. Mutation screening of the COL4A5 gene identified a splicing mutation, c.4688G4A. The proband and his paternal grandmother showed random X chromosome inactivation. However, a preferential expression of the aberrantly spliced transcript was detected in the proband when compared to his grandmother. This finding could explain why the AS phenotype of this 47,XXY boy resembles more an affected male than a female carrier. This is the first reported case of concurrence of Alport and Klinefelter syndromes.

show abstract

“…Karyotypic variations involving mosaic gains or losses of the fragile X chromosome have been observed (Figure 5). Several reports observe these mosaics at higher than expected levels and are likely under-reported owing to the absence of associated cytogenetic studies (Fryns and Van den Berghe, 1988;Santos et al, 2003;Dobkin et al, 2009). Both germline and somatic karyotypic anomalies arise in individuals with CGG-expanded FMR1 X-chromosomes.…”

Section: Unusual Heritability/segregation and Karyotypic Anomaliesmentioning

confidence: 97%

“…Non-mosaic instances of such anomalies have also been reported, with cells having only 47,FRAXA, FRAXA,Y; 46,FRAXA,X ( Filippi et al, 1988 ; Kupke et al, 1991 ), or 47,FRAXA,X,X ( Fuster et al, 1988 ; Tejada et al, 1994 ; Dobkin et al, 2009 ). These cases can arise via either maternal or paternal X-chromosome non-disjunction of the CGG-expanded fragile X chromosome ( Santos et al, 2003 ; Dobkin et al, 2009 ). Mosaicism occurs when the non-disjunction arises post-zygotically, whereas non-disjunction during meiosis will give rise to homogeneous cell populations.…”

Section: Characteristics Of Fragile Sitesmentioning

confidence: 99%

Fragile sites, chromosomal lesions, tandem repeats, and disease

Mirceta

Shum²,

Schmidt³

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

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.

show abstract

Concurrence of fragile X and Klinefelter syndromes: report of a new case of paternal nondisjunction

Cited by 3 publications

References 15 publications

Folate deficiency drives mitotic missegregation of the human FRAXA locus

Folate deficiency drives mitotic missegregation of the human FRAXA locus

Male-to-male transmission of X-linked Alport syndrome in a boy with a 47,XXY karyotype

Fragile sites, chromosomal lesions, tandem repeats, and disease

Contact Info

Product

Resources

About