Prepared by Rania Naoufal MD Learning Objectives Chromosome structure Chromatin Chromatin exists in several alternative configurations depending on what that particular stretch of DNA is doing ID: 1000132
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1. Chromosomes and their disordersPrepared by Rania Naoufal, M.D.
2. Learning Objectives
3. Chromosome structure
4. ChromatinChromatin exists in several alternative configurations, depending on what that particular stretch of DNA is doingThe nucleosome can be loosely or tightly packed, depending on whether the genes in that stretch of DNA are being expressed or notWhen cells are dividing the chromatin is much more tightly packaged
5. Centromeres and telomeres
6. The behavior of chromosomes during cell divisionThe primary function of chromosomes is to allow cells to distribute their DNA to daughter cells in an orderly fashionCell cycle and mitosis: https://youtube.com/watch?v=7NM-UWFHG18&feature=shareCell division of meiosis and mitosis: https://youtube.com/watch?v=A-mFPZLLbHI&feature=share
7. Chromosome abnormalitiesAbnormalities of chromosomes may be either numerical or structural and may involve one or more autosomes, sex chromosomes or both simultaneouslyAneuploidy is an abnormal chromosome number due to an extra or missing chromosomeStructural abnormalities are rearrangements involving one or more chromosomes. Depending on whether or not a structural rearrangement leads to an imbalance of genomic content, these may or may not have a phenotypic effect
8. Balance and imbalance
9. Gene dosageThe central concept for thinking about chromosomes and genomic disorders is that of gene dosage and its balance or imbalanceThe relative dosage of these genes is crucial for normal development. One or three doses instead of two is generally not conductive to normal functionPredicting outcomes for chromosomal and genomic disorders can be an enormous challenge for genetic counseling, particularly in the prenatal setting
10. Numerical abnormalitiesErrors of ploidyErrors where there are wrong number of complete sets of chromosomesNormal cells are diploid (2n = 46 chromosomes)Gametes are haploid (n = 23). Occasionally two sperm fertilize one egg producing a triploid (3n = 69). Triploids can also be produced is the meiotic process fails, resulting in a diploid gamete that then fertilizes a normal haploid gamete Tetraploidy results when a cell replicates its DNA but then does not divide
11. Numerical abnormalitiesAneuploidy Aneuploid cells have just one or more single chromosome extra or missing. Cells or people with aneuploidy are trisomic or monosomic for that chromosome. Autosomal trisomies: Down syndrome - trisomy 21, is the only autosomal trisomy compatible with survival into adult life. Affected babies with Edwards syndrome - trisomy 18, or Patau syndrome -trisomy 13, normally die within the first year of life.Sex chromosome abnormalities: having wrong number of sex chromosomes is much less deleterious than having wrong number of autosomes: 45,X Turner Syndrome, 47,XXY Klinefelter syndrome
12. Structural abnormalitiesReciprocal translocationsArise when any two chromosomes swap non-homologous segmentsA carrier of a balanced reciprocal translocation is at risk of producing offspring with trisomy of one of the translocated segments, and at the same time, monosomy of the other The risk is lower with male translocation carriers than females, because abnormal sperm are less likely to win the race to fertilize the egg
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14. Structural abnormalitiesRobertsonian translocationsInvolve a translocation between two acrocentric chromosomes (13, 14, 15, 21, 22, and Y) with the breakpoint in the proximal short arm, just above the centromereA carrier of a robertsonian translocation is at risk of producing a conceptus with either complete trisomy or complete monosomy for one of the chromosomes
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17. Structural abnormalitiesDeletionsCan be interstitial or terminal, though a chromosome must always have telomeres, so any stable terminal deletion must have somehow acquired a telomere
18. Structural abnormalitiesDeletionsA carrier of a chromosomal deletion is monosomic for the genetic information on the corresponding segment of the normal homologous chromosome. The clinical consequences generally reflect haploinsufficiency (the inability of a single copy of a genetic material to carry out the functions normally performed by two copies)
19. Structural abnormalitiesDuplicationsIn general, they appear to be less harmful than deletions. However, because duplications in a gamete results in chromosomal imbalance, and because the chromosome breaks that generates it might disrupt genes, duplications often lead to some phenotypic abnormalities.
20. Structural abnormalitiesInversionsIf they involve the centromere (pericentric inversion) they change the overall chromosome shape, if not (paracentric inversion) they can only be detected by careful examination of the banding pattern
21. Structural abnormalitiesInsertionsA type of nonreciprocal translocation that occurs when a segment removed from one chromosome is inserted into a different chromosome
22. Structural abnormalitiesRing ChromosomeOccurs when two breaks are created in one chromosome and the resulting ends fuse to form a ring
23. Structural abnormalitiesMarker chromosomes Supernumary marker chromosomes are structurally abnormal chromosome fragments that cannot be characterized fully by conventional cytogenetic techniquesThese centric chromosomes can originate from any of the 24 chromosomes
24. Copy Number VariantsDeletions and duplications of chromosomal segments large enough to be visible under the microscope have severe, often lethal, effectsThe new technique of comparative genomic hybridization revealed deletions and duplications ranging from a few nucleotides up to 1 megabase (1 million nucleotides) are common in normal people
25. Constitutional and mosaic abnormalitiesAny genetic variant can be present either in its constitutional form (present in every cell of a person) or in it mosaic form (present only in some cells)Individuals who are mosaic for a certain abnormality, such as mosaic Down syndrome or mosaic Turner syndrome, are less severely affected than non-mosaic individuals
26. Mechanisms of chromosome abnormalities
27. Disorders due to abnormal chromosome segregation (nondisjunction) Meiotic nondisjunction is the main chromosomal mechanism resulting in aneuploidy This refers to the failure of a pair of chromosomes to disjoin properly during one of the two meiotic divisions
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29. Disorders due to abnormal chromosome segregation (nondisjunction) cont.Nondisjunction can also occur in a mitotic division after formation of the zygoteIf this happens at an early cleavage division, clinically significant mosaicism may resultIn some malignant cell lines and some cell cultures, mitotic nondisjunction can lead to highly abnormal karyotypes
30. Uniparental disomy Chromosome nondisjunction most commonly results in trisomy or monosomy for the particular chromosome involved in the segregation errorHowever, less commonly, it can also lead to a disomic state in which both copies of a chromosome derive from the same parent, rather than one copy being inherited from the mother and the other from the father This situation, called uniparental disomy, is defined as the presence of a disomic cell line containing two chromosomes, that are inherited from only one parent
31. Trisomy rescue
32. Disorders due to recurrent chromosomal syndromes, involving deletions or duplications at genomic hot spotsDozens of syndromes characterized by developmental delay, intellectual disability, and a specific constellation of dysmorphic defects and birth defects are known to be associated with recurrent subchromosomal abnormalities These syndromes are usually too small to be visible in standard karyotype analysis, are referred to microdeletions and microduplication syndromesA particularly common microdeletion involves chromosome 22q11.2, illustrates such genomic disorders
33. Disorders due to recurrent chromosomal syndromes, involving deletions or duplications at genomic hot spots cont.High-resolution genomic studies have demonstrated the presence of genomic sequences that predispose to the rearrangementsThe breakpoints localize to low-copy repeated sequences in the genome termed segmental duplications Aberrant recombination between nearby copies of the repats causes the deletion and/or duplication, which typically spans several hundred to thousands of base pairs
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35. Disorders due to idiopathic chromosomal abnormalities, typically de novoWhereas the abnormalities just described are mediated by the landscape of specific genomic features in particular chromosomal regions, many other chromosome abnormalities are due to deletions or rearrangements that have no definitive mechanistic basis Most of these have been seen in only a few patients and are not associated with recognized clinical syndromes
36. Disorders due to unbalanced familial chromosomal abnormalitiesAlthough most of the idiopathic abnormalities just described are sporadic, other clinical presentations can occur because of unbalanced segregation of familial chromosome abnormalitiesIn these cases, the underlying mechanism for the clinical phenotype is not the chromosomal abnormality itself, but rather its transmission in an unbalanced state from a parent who is a balanced carrier to the subsequent generation
37. Disorders due to unbalanced familial chromosomal abnormalities cont.In the case of balanced translocations, for example, because the chromosomes involved form a quadrivalent in meiosis, the particular combination of chromosomes transmitted to a given gamete can lead to genomic imbalance, even though the segregation is itself normalAnother type of familial structural abnormality that illustrates this mechanism involves inversion chromosomes
38. Disorders due to chromosomal and genomic events that reveal regions of genomic imprintingFor some disorders, the expression of the disease phenotype depends on whether the mutant allele or abnormal chromosome has been inherited from the father or from the motherSuch parent-of-origin effects are the result of genomic imprintingThe hallmark of imprinted genes that distinguishes them from other autosomal loci is that only one allele, either maternal or paternal, is expressed in the relevant tissue
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40. Article to readShaffer, L. G., Bejjani, B. (2011). Development of new postnatal diagnostic methods for chromosome disorders. Seminars in Fetal & Neonatal Medicine, 16(2):114-8. doi: 10.1016/j.siny.2010.11.001.Matin, C. L., Warburton, D. (2015). Detection of Chromosomal Aberrations in Clinical Practice: From Karyotype to Genome Sequence. Annual review of genomics and human genetics, 6:309-26. doi: 10.1146/annurev-genom-090413-025346.