Chromosomal instability syndromes

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Diseases associated with impaired DNA repair, more commonly called chromosomal instability syndromes or syndromes associated with increased fragility of chromosomes show some common features. These are autosomal recessive syndromes associated with increased sensitivity to UV radiation and other mutagens. They are often associated with hyper or hypopigmentation, short stature and an immune defect. The high sensitivity of patients to mutagens is associated with an increased level of chromatid and chromosome breaks and chromosome exchanges in their cells. In some diseases, these changes are specific (e.g. increased level of sister chromatid exchanges and exchanges between homologous chromosomes in Bloom syndrome, specific breaks on chromosome 7 and 14 in ataxia telangiectasia and Nijmegen breakage syndrome). The level of acquired chromosomal aberrations is increased spontaneously, or the patient’s cells are more sensitive to the in vitro induction of aberrations by mutagens. Because this is a repair or replication disorder, patients have a multifold increased risk of developing cancer.

Fragile syndromes – chromosomal instability syndromes
Title/Abbreviation Clinical manifestations Cytogenetic findings; increased level Disorder Genes
Ataxia telangiectasia (Luis-Bar sy; AT) Cerebellar ataxia, telangiectasia, growth retardation, hypogonadism, combined immunodeficiency, predisposition to malignancies chromosome breaks and exchanges, especially in chromosomes 7, 14, ev. 2 and 22 (immunoglobulin gene and T-cell receptor gene regions) Defect in signal recognition for repair (double-stranded DNA breaks=DSBs) ATM
Bloom syndrome (BS) Dwarfism, hyperpigmentation, butterfly rash on the face, immunodeficiency, predisposition to tumors chromosome breaks, exchanges between homologous chromosomes, sister chromatid exchanges (SCEs) DNA helicase — DNA replication and repair BLM
Fanconi anemia (FA) Growth retardation, pancytopenia, skeletal abnormalities, brown skin, no immunodeficiency, predisposition to leukemia and other malignancies Chromosome breaks and exchanges Excision repair, repair of UV damage Heterogenous:

7 complementation group (A-G) genes: FANCA, FANCC, FANCD2, FANCE, FANCG Non-localized genes: FANCB, FANCD1

Xeroderma pigmentosum (XP) Extreme sensitivity to sunlight, skin changes, neurological dysfunctions, mental retardation, predisposition to tumors, especially of the skin Spontaneous level not increased, chromosome breaks, sister chromatid exchanges after induction (especially UV radiation) Nucleotide excision repair (NER) except XPV form — DNA polymerase H Heterogenous:

7 complementation groups (A-G) + variant form genes: XPA, XPB (ERCC3), XPC, XPD (ERCC2), XPE, XPF (ERCC4), XPG (ERCC5), XPV (Pol eta)

Nijmegen breakage syndrome (NBS) Growth, mental retardation, microcephalic, dysmorphia, immunodeficiency, predisposition especially to lymphoid malignancies Breaks and changes, especially of chromosomes 7,14 (regions of immunoglobulin genes and genes for T lymphocyte receptors) Repair of DNA double-strand breaks NBS1 – nibrin

A cytogenetic affect (increased chromosomal instability) and an increased risk of tumors are also shown by syndromes associated with premature aging such as Werner’s syndrome (cataract, subcutaneous calcification, skin changes, premature graying, premature arteriolosclerosis – WRN gene – DNA helicase/exonuclease RECQL2) a Cockayne syndrome (dwarfism, mental retardation, deafness, premature senility – genes CSA (ERCC8), CSB (ERCC6)), in patients also expressing symptoms of xeroderma pigmentosum (XP/CS) genes XPB (ERCC3), XPD (ERCC2), XPG (ERCC5).

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