9 - Clinical Cytogenetics.pptx.pdf

Clinical Cytogenetics Cytogenetic abnormalities Dr. Madona Akhobadze 2024 Clinical Cytogenetics: Disorders of the Autosomes and the Sex Chromosomes. Autosomal Disorders. The Sex Chromosomes and Their Abnormalities. Disorders...

Clinical Cytogenetics Cytogenetic abnormalities Dr. Madona Akhobadze 2024 Clinical Cytogenetics: Disorders of the Autosomes and the Sex Chromosomes. Autosomal Disorders. The Sex Chromosomes and Their Abnormalities. Disorders of Gonadal and Sexual Development Reading: Ch. 6 - Thompson & Thompson Genetics in Medicine, Robert L. Nussbaum, Roderick R. McInnes General Features of Chromosomal Disorders associated with absence (deletion, monosomy), excess (trisomy), or abnormal rearrangements (translocations) of chromosomes loss of chromosomal material produces more severe defects than does a gain Excess chromosomal material – complete chromosome (trisomy) or part of chromosome (Robertsonian translocation) Imbalances of sex chromosomes are tolerated much better than imbalances of autosomes Sex chromosomal disorders - subtle abnormalities, not detected at birth De novo changes AUTOSOMAL DISORDERS numerous rare chromosome disorders in which gain or loss of an entire chromosome or a chromosome segment only in fetuses that were aborted spontaneously or involve relatively short chromosome segments three well-defined non-mosaic chromosome disorders compatible with postnatal survival Cytogenetic Disorders Involving Autosomes autosomal trisomies: Trisomy 21 - Down Syndrome Trisomy 18 - Edwards Syndrome Trisomy 13 - Patau syndrome Deletion syndrome: partial deletion of the short arm of chromosome 5 - cri du chat syndrome AUTOSOMAL DISORDERS growth retardation, mental retardation, and multiple congenital anomalies Trisomy 21 - Down Syndrome 95% of affected persons have trisomy 21, chromosome count is 47 meiotic nondisjunction parents of such children are normal in all respects 1/1550 live births in women younger than 20 years 1/25 live births in women older than 45 years maternal origin 4% have extra chromosomal - translocation of the long arm of chromosome 21 to chromosome 22 or 14. translocated chromosome is inherited from one of the parents, who is a carrier of a Robertsonian translocation. 1% of patients with trisomy 21 are mosaics, having a mixture of 46- and 47-chromosome cells Diagnostic clinical features Flat facial profile, oblique palpebral fissures, and epicanthic folds congenital heart disease - defects of the endocardial cushion, including atrial septal defects, atrioventricular valve malformations, and ventricular septal defects atresias of the esophagus and small bowel increased risk of developing acute leukemia older than age 40 develop neuropathologic changes characteristic of Alzheimer disease Abnormal immune responses that predispose them to serious infections DOWN SYNDROME trisomy 21 the most common and best known of the chromosome disorders and is the single most common genetic cause of moderate mental retardation 1/800 born with Down syndrome among liveborn children or fetuses of mothers 35 years of age or older, the incidence rate is far higher DOWN SYNDROME Langdon Down in 1866 Increased maternal age and a peculiar distribution within families concordance in monozygotic twins almost complete discordance in dizygotic twins and other family members DOWN SYNDROME - PHENOTYPE diagnosed at birth or shortly after by its dysmorphic features Hypotonia – first abnormality noticed in the newborn dysmorphic facial features short in stature brachycephaly with a flat occiput neck is short, with loose skin on the nape DOWN SYNDROME - PHENOTYPE nasal bridge is flat ears are low-set, folded appearance eyes have Brushfield spots around the margin of the iris mouth is open, often showing a furrowed, protruding tongue epicanthal folds and upslanting palpebral fissures gave rise to the term mongolism DOWN SYNDROME - PHENOTYPE hands are short and broad with a single transverse palmar crease - “simian crease” incurved fifth digits, or clinodactyly dermatoglyphics – patterns of the ridged skin are highly characteristic feet show a wide gap between the first and second toes, with a furrow extending proximally on the plantar surface DOWN SYNDROME - PHENOTYPE mental retardation early infancy the child may not seem delayed in development, the delay is usually obvious by the end of the first year The intelligence quotient (IQ) - 30 to 60 when the child is old enough to be tested develop into happy, responsive, and even self-reliant persons in spite of these limitations DOWN SYNDROME - PHENOTYPE Congenital heart disease - 1/3 higher proportion of abortuses with the syndrome malformations, such as duodenal atresia and tracheoesophageal fistula high degree of variability in the phenotype specific abnormalities are detected in almost all patients, others are seen only in a subset of cases DOWN SYNDROME - PRENATAL AND POSTNATAL SURVIVAL half of all abnormalities identified prenatally in amniocentesis, and in chorionic villus sampling at different maternal ages can provide a basis for estimating the amount of fetal loss between the 11th and 16th weeks and between the 16th week and birth all maternal ages, there is some loss between the 11th and 16th weeks additional loss later in pregnancy only 20% to 25% of trisomy 21 conceptuses survive to birth DOWN SYNDROME - PRENATAL AND POSTNATAL SURVIVAL ¼ of the liveborn infants with heart defects die before their first birthday 15-fold increase in the risk of leukemia Premature dementia, associated with the neuropathological findings characteristic of Alzheimer disease (cortical atrophy, ventricular dilatation, and neurofibrillary tangles), affects nearly all Down syndrome patients, several decades earlier than the typical age at onset of Alzheimer disease in the general population DOWN SYNDROME - THE CHROMOSOMES IN DOWN SYNDROME trisomy 21 Robertsonian Translocation 21q21q Translocation Mosaic Down Syndrome Partial Trisomy 21 DOWN SYNDROME - TRISOMY 21 95% of all patients meiotic nondisjunction of the chromosome 21 pair during maternal meiosis 90% of cases predominantly in meiosis I about 10% of cases occur in paternal meiosis in meiosis II DOWN SYNDROME - ROBERTSONIAN TRANSLOCATION 4% of Down syndrome patients have 46 chromosomes Robertsonian translocation between chromosome 21q and the long arm of one of the other acrocentric chromosomes (usually chromosome 14 or 22) no relation to maternal age high recurrence risk in families when a parent, especially the mother, is a carrier of the translocation DOWN SYNDROME - 21Q21Q TRANSLOCATION composed of two chromosome 21 long arms recurrence risk is low DOWN SYNDROME - MOSAIC DOWN SYNDROME 2% of Down syndrome patients phenotype may be milder than that of typical trisomy 21 wide variability in phenotypes DOWN SYNDROME - PARTIAL TRISOMY 21 very rare only a part of the long arm of chromosome 21 is present in triplicate patient with no cytogenetically visible chromosome abnormality is even more rarely identified Trisomy 18 - Edwards Syndrome 1/5,000 small head, small jaw, clenched fists with overlapping fingers, and severe intellectual disability Trisomy 18 - Edwards Syndrome kidney malformations, structural heart defects at birth (ventricular septal defect, atrial septal defect, patent ductus arteriosus), intestines protruding outside the body (omphalocele), esophageal atresia, intellectual disability, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, and arthrogryposis (contractures) Trisomy 18 - Edwards Syndrome Microcephaly, low-set, malformed ears, micrognathia, cleft lip/cleft palate, upturned nose, narrow eyelid folds (palpebral fissures), hypertelorism, blepharoptosis, short breast bone, clenched hands, choroid plexus cysts, underdeveloped thumbs and/or nails, absent radius, webbing of the second and third toes, clubfoot or rocker bottom feet, and in males, undescended testicles. Trisomy 13 - Patau syndrome Nervous system - Intellectual disability and motor disorder, Microcephaly, Holoprosencephaly, Structural eye defects, including microphthalmia, Peters' anomaly, cataract, iris or fundus (coloboma), retinal dysplasia or retinal detachment, sensory nystagmus, cortical visual loss, and optic nerve hypoplasia, Meningomyelocele Trisomy 13 Patau syndrome Musculoskeletal and cutaneous – Polydactyly, Low-set ears, Prominent heel, Deformed feet known as rocker-bottom feet, Omphalocele, Overlapping of fingers over thumb, Cutis aplasia, Cleft palate Trisomy 13 Patau syndrome Urogenital – Abnormal genitalia, Kidney defects Heart defects – ventricular septal defect, Patent Ductus Arteriosus, Dextrocardia, Single umbilical artery Cri du Chat Syndrome either a terminal or interstitial deletion of part of the short arm of chromosome 5 crying infants with this disorder sound like a mewing cat 1% of all institutionalized mentally retarded patients microcephaly, hypertelorism, epicanthal folds, low-set ears sometimes with preauricular tags, and micrognathia 22q11.2 Deletion Syndrome - DiGeorge syndrome small interstitial deletion of band 11 on the long arm of chromosome 22 congenital heart disease affecting the outfow tracts, abnormalities of the palate, facial dysmorphism, developmental delay, thymic hypoplasia with impaired T cell immunity and parathyroid hypoplasia resulting in hypocalcemia T cell immunodeficiency and hypocalcemia are the dominant 22q11.2 Deletion Syndrome - Velocardiofacial syndrome Velocardiocacial syndrome - mild immunodeficiency and pronounced dysmorphology and cardiac defects High risk for schizophrenia and bipolar disorder fuorescence in situ hybridization (FISH) testis-determ ining factor (TDF) Cytogenetic Disorders Involving Sex Chromosomes - Klinefelter Syndrome Male hypogonadism that develops when there are at least two X chromosomes and one or more Y chromosomes hypogonadism in males 47,XXY karyotype Distinctive body habitus with an increase in length between the soles and the pubic bone, which creates the appearance of an elongated body – eunuchoid body habitus. Cytogenetic Disorders Involving Sex Chromosomes - Klinefelter Syndrome Reduced facial, body, and pubic hair and gynecomastia testicular atrophy, the serum testosterone levels are lower than normal, and urinary gonadotropin levels are elevated mental retardation higher frequency of breast cancer, extragonadal germ-cell tumors, and autoimmune diseases such as systemic lupus erythematosus Turner Syndrome primary hypogonadis in phenotypic females results from partial or complete monosomy of the short arm of the X chromosome 45,X and Variants growth retardation, abnormally short stature swelling of the nape of the neck because of distended lymphatic channels (in infancy) - webbing of the neck in older children Turner Syndrome low posterior hairline; cubitus valgus (an increase in the carrying angle of the arms); shield-like chest with widely spaced nipples; high-arched palate; lymphedema of the hands and feet; congenital malformations – horse-shoe kidney, bicuspid aortic valve, and coarctation of the aorta Cardiovascular abnormalities are the most common cause of death in childhood primary amenorrhea - streak ovaries clinical hypothyroidism DISORDERS OF GONADAL AND SEXUAL DEVELOPMENT Both ovarian and testicular tissue is present, a condition known as hermaphroditism Gonadal Dysgenesis Camptomelic dysplasia - due to mutations in the SOX9 gene on chromosome 17q, is an autosomal dominant disorder with usually lethal skeletal malformations DISORDERS OF GONADAL AND SEXUAL DEVELOPMENT Chromosomally male patients with Denys-Drash syndrome have ambiguous external genitalia patients with the more severe Frasier syndrome show XY complete gonadal dysgenesis Female Pseudohermaphroditism have gonadal tissue of only one sex that matches their chromosomal constitution 46,XX karyotypes with normal ovarian tissue but with ambiguous or male external genitalia congenital adrenal hyperplasia (CAH) defects in enzymes of the adrenal cortex required for cortisol biosynthesis and resulting in virilization of female infants Male Pseudohermaphroditism disorders of testis formation during embryological development 46,XY with incompletely masculinized or female external genitalia abnormalities of gonadotropins, inherited disorders of testosterone biosynthesis and metabolism abnormalities of androgen target cells X-linked syndrome known as androgen insensitivity syndrome (testicular feminization) SINGLE-GENE DISORDERS WITH ATYPICAL PATTERNS OF INHERITANCE Diseases caused by triplet repeat mutations Diseases caused by mutations in mitochondrial genes Diseases associated with alteration of imprinted regions of the genome  Fragile X Syndrome causative mutation occurs in a long repeating sequence of three nucleotides Huntington disease and myotonic dystrophy associated with neurodegenerative changes 1/1550 for males and 1/8000 for females autism-like symptoms long face with a large mandible, large everted ears, and large testicles – macroorchidism Carrier males - Affected females Anticipation - clinical features of fragile X syndrome worsen with each successive generation Fragile X tremor/ataxia resulting from expression of a FMR1 gene bearing premutation develops in some males and females. The accumulation of corresponding mRNA in the nucleus binds and sequesters certain proteins that are essential for normal neuronal functions  Diseases Caused by Mutations in Mitochondrial Genes maternal inheritance mitochondrial DNA of the zygote is derived entirely from the ovum mothers transmit mitochondrial genes to their offspring, both male and female affect organs most dependent on oxidative phosphorylation - CNS, skeletal muscle, cardiac muscle, liver, and kidney Leber hereditary optic neuropathy – neurodegenerative disease manifests as progressive bilateral loss of central vision that leads in due course to blindness Prader-Willi Syndrome functional differences exist between the paternal and the maternal copies of some genes Genomic imprinting - certain homologous genes are differentially inactivated during paternal and maternal gametogenesis Prader-Willi - deletion of paternal chromosomal region 15q12 - mental retardation, short stature, hypotonia, obesity, small hands and feet, hypogonadism Angelman Syndrome Angelman - deletion of maternal chromosomal region 15q12 - mentally retarded, ataxic gait, seizures and inappropriate laughter - happy puppet syndrome გმადლობთ , ყურადღებისთვის !!!