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Chromosomal Basis of Human Diseases

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Chromosomal Basis of Human Diseases CHROMOSOMAL BASIS OF HUMAN DISEASES History of human cytogenetics The “Trisomy Period” The “Banding Era Historically, cytogenetics was developed before molecular genetics.Cytogenetics is Introduction of different banding a brench of genetics concerned with the techniques enabled the study of the structure and function of identification each chromosome chromosomes. The visualization of and the detection of chromosomes and correct model human chromosomal abnormalities, chromosome number was determined by such as translocations, Тjio and Levan in 1956. inversions, deletions and They serendipitously used hypotonic insertions. solution for releasing chromosomes from cells. History of human cytogenetics The “Molecular Era” Molecular karyotyping FISH Аrray-based CGH Chomosome-based CGH The major technique in molecular cytogenetics is fluorescent in situ hybridization (FISH), which is an approach that allows nucleic acid sequence to be examined inside cells or on chromosomes. In 2003 the “so-called” array techniques were introduced in genetic diagnostics, providing high resolution for the determination of chromosomal gain or loss. Formal cytogenetics – group of chromosomes Human chromosomes are classified by position of centromere into: metacentric, submetacentric, acrocentric. There are 22 paires of autosomes and a pair of sex chromosomes – XX or XY. Formal cytogenetics – nomenclature An ideogram represents the typical chromosome pattern and the relation of the p and q arm. Databases that can help to identify a syndrome 1. Elements of Morphology: helps to find the right terminology for subsequent literature and database search Free: http://elementsofmorphology.nih.gov/index.cgi 2. Phenomizer: postnatal, to find a syndrome based on combination of several malformations/dysmorphic signs Free: http://compbio.charite.de/phenomizer/ 3. Phenotip: prenatal, find a syndrome from the combination of several malformations/dysmorphic signs Free: http://www.phenotip.com/ 4. Orphanet: postnatal, find a syndrome, get information on diagnostics and other support, in diff. languages Free: http://www.orpha.net/consor/cgi-bin/index.php?lng=EN 5. Other commercial databases Face2Gene: http://www.fdna.com/ London Dysmorphology Database: http://www.lmdatabases.com POSSUM: http://www.possum.net.au/ Indications for karyotype study • Diagnose of constitutional disorders – disorders present at birth (birth defects, ambiguous genitalia) – intellectual disability and physical development delay – adults with reproductive failure – fetal chromosome diagnosis (preimplantaion/prenatal diagnostics) • Diagnose of an acquired disorders – most commonly haematological malignancies and solid tumor – evaluation of chromosome aberrations in mutagenesis (in vitro) Mutation types Genome mutation (chromosome number) Chromosome mutation (chromosome structure) Gene mutation (DNA sequence) Genome mutation is total number of chromosomes is changed due to errors during gametogenesis in meiotic nondisjunction Paternal % Maternal % Trisomy 13 5 85 Trisomy 18 10 90 Trisomy 21 5 95 45,X 80 20 47,XXX 5 95 47,XXY 45 55 47,XYY 100 0 Non-disjunction more frequent in (older) women genome mutations Point mutations more frequent in (older) male gene mutations Chromosome Abnormalities Numerical Structural Chromosome changes result from errors occurring during meiotic or mitotic segregation. Two classes of Aneuploidy numerical chromosomal Chromosome loss or gain abnormalities can be distinguished. • Trisomy – having three copies of a particular chromosome • Monosomy - corresponds to lack Triploidy of a chromosome Three haploid set (23xn) very seldom survive to term, and the condition is not compatible with life. AUTOSOMAL TRISOMIES Trisomy 21: Down syndrome- Trisomy 13: Patau Trisomy 18: Edwards 47,XX+21 syndrome - 47,XX,+13 syndrome – 47,XX +18 • microcephaly impairment of cognitive ability • polyductily • severe psychomotor and • stunted growth • cleft palate, cleft lip growth retardation, • redundant neck skin • holoprosencephaly • growth deficiency • flat face (failure of the forebrain to divide • structural heart defects • epicantus properly) • micrognatia (small jaw) • flat nasal bridge • low vitality • narrow eyelid folds • flat neck • incidence 1:11000 palbebral fissures • heart defect • webbing of the 2-nd and 3-d • semian crease fingers • incidence 1:700 The critical region has • microcephaly been reported to include • feeding, breathing difficulties Molecular analysis has revealed that 13q14-13q32 with • low vitality the 21q22.1-q22.3 region appears to variable expression, contain the gene(s) responsible for the • incidence 1:15000 congenital heart disease observed in gene interactions, or Down syndrome. interchromosomal 95% of the cases of trisomy 21 the effects. extra chromosome comes from the mother and only in 5% from the father. SEX-CHROMOSOME ANEUPLOIDIES • Turner syndrome: inherit only one X chromosome; their genotype is X0. • Triple-X females: inherit three X chromosomes; their genotype is XXX or more rarely XXXX. Some of them are fertile. • Klinefelter syndrome: males inherit one or more extra X chromosomes; their genotype is XXY or more rarely XXXY, XXXXY, or XY/XXY mosaic (hypogonadism, increased stature, infertility, gynecomastia, physical and behavioral differences) • Jacobs syndrome:males inherit an extra Y chromosome; their genotype is XYY (increased growth velocity, some of them are fertile, half of 47,XYY boys have learning difficulties) The increased gene dosage of three X/Y chromosome pseudoautosomal region (PAR1) SHOX genes has been postulated as a cause of the increased stature seen in all three sex chromosome trisomies: 47,XXX, 47,XXY, and 47,XYY. 10 X-Y related syndromes Turner syndrome is the only monosomy in liveborn. However Klinefelter’s syndrome – 47.XXY the syndrome presents with different karyotypes 45,X; 46,XX/45,X; 46,Xi(Xq) • Wide or weblike neck • Receding or small lower jaw • High, narrow roof of the mouth (palate) • Low-set ears • Low hairline at the back of the head • hypogonadism • Broad chest with widely spaced nipples • increased stature • Short fingers and toes • infertility • Arms that turn outward at the elbows • physical and behavioral • Fingernails and toenails that are narrow differences and turned upward • gynecomastia • Swelling of the hands and feet, especially at birth • Slightly smaller than average height at birth • Delayed growth Frequency of cytogenetic aberrations • ~50% of abortions show chromosomal abnormalities • 1 in 120 newborn have chromosomal aberrations, ~50% of them are of clinical relevance. trisomy 13 0.08% sSMC 0.4% trisomy 18 0.15% 45,X 0.3% trisomy 21 1.2% XXX 1.1% triploidy 0.02% unbalanced structural aberr. 0.3% XXY 1.2% balanced rec. translocation 2.5% XYY 1.2% balanced Robertsonian transl. 1.0% other aneupl. 0.15% I nversions 0.8% • cause for early sudden infant death (5-7%, most frequently trisomy 18 and 21) • mentally retarded individuals (without FRA-X-syndrome): IQ < 20 3-10% most frequent: IQ = 20-49 12-35% Down-syndrome, IQ = 50-69 3% deletions/ microdeletions, unbalanced rtanslocations… • in infertile individuals, hermaphroditism, recurrent abortions etc. Structural Chromosome Rearrangements Balanced Unbalanced is a structural chromosomal there is a gain or loss of abnormalities if there is no gain or chromosome material loss of chromosome material translocations inversions • insertion • deletion • duplication reciprocal robertsonian • ring • dicentric • isochromosome TYPES OF CHROMOSOME ABERRATIONS arised from gamets and somatic cells Constitutional chromosomal Acquired chromosomal aberrations anomalies They result from chromosome On the other hand, any breakage with subsequent changes in the chromosomes reunion in a different which arise during configuration. Chromosomal development or during the life rearrangements originating in of an organism are referred as the germ line, whether inherited acquired chromosomal from the parents or from a de rearrangements novo mutation in the gametes, are referred to as constitutional INVERSION PARACENTRIC INVERSION PERICENTRIC INVERSION If the inversion is outside An inversion involves two breaks the centromere, it is in a chromosome and the termed a paracentric segment is reversed or inverted inversion whereas inversion in the position spanning the centromere, involving both the chromosome arms, is known as pericentric inversion. ՌԵՑԻՊՐՈԿ ՏՐԱՆՍԼՈԿԱՑԻԱ ՔՐՈՄՈՍՈՄՆԵՐԻ ՏԱՐԱԲԱՇԽՈՒՄԸ ԳԱՄԵՏՆԵՐՈՒՄ ԿՐԵԼԻՈՒԹՅԱՆ ԴԵՊՔՈՒՄ A carrier of a balanced reciprocal translocation can produce gametes that give rise to an entirely normal child, a phenotypically normal balanced carrier, or various unbalanced karyotypes ISCN - International System for Human Cytogenetic Nomenclature • most recent edition pub. 2016 • provides standardized “grammatical” rules for the designation of cytogenetic findings A uniform system of chromosomal classification is internationally accepted for identification.The pattern of bands on each chromosome is numbered on each arm. By this numbering, location of any band, DNA sequences and genes within it, and its involvement in a chromosome abnormality can be precisely described. Example: 46,XY,der(9)(9qter→9p23:: ::4q26→4qter),pat CLINICAL CASE: Partial trisomy 4q26-qter as a result of a reciprocal translocation in parent Various ocular abnormalities are presented. Ophthalmologic assessment revealed: divergent strabismus, microphtalmiа, optic nerve subatrophy,retina atrophy, locus oculosum with searching look. Others include receding jaw, pointed chin highly
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