* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Cytogenetics
Public health genomics wikipedia , lookup
BRCA mutation wikipedia , lookup
Cell-free fetal DNA wikipedia , lookup
Designer baby wikipedia , lookup
Y chromosome wikipedia , lookup
Saethre–Chotzen syndrome wikipedia , lookup
Genomic imprinting wikipedia , lookup
Birth defect wikipedia , lookup
Microevolution wikipedia , lookup
X-inactivation wikipedia , lookup
Oncogenomics wikipedia , lookup
Neocentromere wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Polydactyly wikipedia , lookup
Medical genetics wikipedia , lookup
Frontonasal dysplasia wikipedia , lookup
Genome (book) wikipedia , lookup
Williams syndrome wikipedia , lookup
DiGeorge syndrome wikipedia , lookup
Cytogenetics Dr Alice S Chau Cytogenetics = Study of chromosomes and their abnormalities Karyotypes Display of chromosomes in the order according to length and shape The latter depends on the position of the centromere at the metaphase: 1. Metacentric 2. Submetacentric 3. acrocentric Different chromosome karyotypes Metacentric Submetacentric Acrocentric Short Arm p satellite Long Arm q A normal female karyotype – 46, XX Disorders of chromosomes Normal female karyotype = 46, XX Normal male karyoptye = 46, XY (1) Numerical abnormalities Aneuploids – failure of separation of paired chromosomes at cell division (a) Trisomy e.g. (+21) (b) Monosomy e.g. (-X) (c) Triploidy, Tetraploidy e.g. (69, 92 chromosomes) Disorders of chromosomes (2) Structural Disorders (a)Translocation – (t) : reciprocal exchange of chromosome segment (b) Deletion – (del) : loss of genetic material (c) Duplication – (dup) : extra copy of chromosome region (d) Isochromosome – (i) : duplication of one arm and lack of others (e) Ring chromosome – (r) : abnormal repair at distal segment to form a ring Chromosome abnormalities (1) Autosomal syndromes Trisomy 21 (Down syndrome) 47, XY, +21 Trisomy 18 (Edwards syndrome) 47, XX, +18 Trisomy 13 (Patau syndrome) 47, XX, +13 Deletion #15 (Prader Willi syndrome) 46, XX, del(15q) (2) Sex chromosome abnormalities Turner syndrome (45, X) Klinefelter syndrome (47, XXY) Fragile-X syndrome Down’s syndrome - face Down’s syndrome – cyanotic TOF Down’s syndrome – 47, XY, +21 Down’s syndrome (Trisomy G) 1. General - Hypotonia; incidence 1 in 668 (or 1.5 per 1,000) 2. Eyes - Upward lateral slanting, inner epicanthic folds, speckling of iris, nystagmus, strabismus 3. CNS - Mental deficiency, I.Q. 25 to 50 4. Cranium - Relatively flat occiput 5. Ears – small, overlapping upper helices, low-set 6. Nose – low nasal bridge, small nose Down’s syndrome (Trisomy G) 7. Mouth – hypoplastic maxilla, protruding tongue 8. Hands – short hands and fingers, Simian crease, dermal: distal triradii, no. of ulnar loops 9. Feet – wide gap at first and second toes 10. Genitalia – small penis, cryptorchidism 11. CVS – A-V communis, VSD, tetralogy of Fallot 12. Related to maternal age – 1 in 2,300 at 15-19 years 1 in 46 at 45 years Relationship of maternal age on risk of Down’s syndrome Maternal age risk 20 years 1 in 1,500 30 years 1 in 900 35 years 1 in 400 40 years 1 in 100 45 years 1 in 30 Down’s inheritance Down’s 45, XX, t 14/21 Down’s 46, XY, -21, +t(21/21) Recurrent risk of Down’s syndrome patient mother father Chance of recurrence (%) Carrier N Carrier N Carrier N Normal C Normal C Normal C 10-15 5 10-15 5 100 100 Trisomy 21 N N 1 Translocation or mosaic N N small D/G translocation 21/22 translocation 21/21 translocation Edward’s syndrome Edward’s syndrome - hand Edward’s syndrome – rocker bottom feet Edward’s syndrome – rocker bottom feet Edward’s syndrome – 11 ribs & TOF Edward’s syndrome – 47, XX, +18 Edwards syndrome (Trisomy E – 47, +18) Mental retardation Failure to thrive Clenched fist Single palmer crease “rocket bottom” foot Deformed ears Congenital heart disease Patau’s syndrome (lateral view) Patau’s syndrome (cleft lip & palate) Patau’s syndrome scalp defect) Patau’s syndrome (polydactyly) Patau’s syndrome (polydactyly) Patau’s syndrome (cryptorchidism) Patau’s syndrome 47, XX, +13 Patau’s syndrome (Trisomy D) 1. General – severe developmental retardation, apnoeic spells, death within 3 months 2. CNS – MD, deafness, minor motor seizures 3. Cranium – sloping of forehead, microcephaly 4. Eyes – microphthalmus and/or colobomata 5. Ears – abnormal helices and/or low-set 6. Mouth – cleft lip and/or palate 7. Hands – polydactyly, trisomy hands, Simian crease Patau’s syndrome (Trisomy D) 8. Feet – polydactyly, posterior prominence of heel 9. Cardiac – VSD, rotational anomaly 10. Abdomen – acessory spleen, large gall-bladder, incomplete rotation of colon 11. Renal – hydronephrosis, polycystic kidney 12. Genitalia : cryptorchism : partially bicornate uterus 13. Incidence – 1 in 5,000 live births, mean maternal age 31.6 years Prader Willi syndrome Prader Willi syndrome Prader Willi syndrome - hands Prader Willi – undescended testes Prader Willi – undescended testes Prader Willi – del 15q- (q11-q13) Prader Willi – del 15q- Prader-Willi syndrome One of the short stature conditions Due to deletion of chromosome 15 (q11-13) and loss of some genes Symptoms: – Short and obese, hypotonic – Face is normal with narrow forehead – Eyes are small and almond-shaped – Hands and feet are fat and small – Hypogonadism – Mental retardation, I.Q. 36 to 85 Turner’s syndrome Turner’s syndrome – low hair line Turner’s syndrome – ankle oedema in neonates Turner’s syndrome – 45, XO Turner syndrome (45, XO) Ovarian dysgenesis Short stature Webbing of neck Primary amenorrhoea Failure of development of secondary sexual characteristics Klinefelter’s syndrome Klinefelter’s syndrome Klinefelter’s syndrome Klinefelter’s syndrome – undescended testes, hypospadia Klinefelter’s syndrome – 47, XXY Klinefelter’s syndrome (47, XXY) 1. External genitalia – delayed puberty or small gonads’ 2. Growth & physical measurement, with gross mental retardation In childhood – normal until puberty, or even taller than control After puberty – with “eunuchoid” propertions, I.e. greater pubis-sole measurement 3. Pubic & facial hair – delayed growing, feminine in distribution Klinefelter’s syndrome (47, XXY) 4. Gynaecomastia – between 14 and 16 years 5. Testes – small or thickened cord-like structure Histology : large clumps of Leydig cells, irregularly arranged seminiferous tubules, which showed hyalinization or sclerosis “ghost tubules”, some may have spermatogenesis 6. Incidence – In newborn: 1.98 per 1,000 births In mental subnormals: 6 to 9 per 1,000 Mean maternal age: 28.7 years Mean paternal age: 30.7 years Fragile X syndrome Fragile X syndrome Familial fragile X syndrome Familial fragile X syndrome Familial fragile X syndrome Fragile X syndrome - ear Fragile X syndrome Fragile X syndrome Fragile X syndrome During harvest, add KCl before staining with Leishman stain, at Xq:- distal end shows 1 or 2 satellite appearance = Fragile site 50-100 cells are examined, a 4% or higher frequency is significant Fragile X syndrome Fragile X syndrome Fragile-X syndrome 1. Mental handicap – moderate to severe MD 2. Macro-orchidism – normal testicular volume is 23 to 25 ml : V = (length) x (width)2 x 6 The testicular functions (hormone level, sperm count and morphology) are normal 3. Facies – high forehead, hypoplasia of middle of face, large mouth and thick lips, large jaws and prominent chin, large ears poorly formed Fragile-X syndrome 4. Speech & language – delayed speech and defective speech, weak auditory reception and sequential memory 5. Behaviour – autistic, shy or fearful 6. Increased birth weight, obese or short Multifactorial Inheritance Dr Alice S Chau Multifactorial inheritance Caused by combination effects of many “genes” and “environmental” factors Environmental Genetic Infection Radiological Chemical Cystic fibrosis Haemophilia Marfan syndrome Examples: body height, intelligence, cleft lip and/or palate, congenital heart disease, coronary heart disease, diabetes mellitus, cancers, schizophrenia & neural tube defect Incidence of genetic disorders Chromosomal abnormalities Single gene mutation Familial Multifactorial inheritance Others & unknown cause 10% 3% 14% 23% 50% Recurrent risks in genetic disorders Single gene disorders – Autosomal dominant 50% – Autosomal recessive 25% Multifactorial inheritance – “empirical risk” – based on direct observation of data, on a large series of affected families, thus calculating the percentage e.g. cleft lip & palate General population = 1/1,000 First degree relative = 4% Second degree relative = 7 per thousand Genes in common Genes in common Monozygotic twins Parent-child, sibling, dizygotic twins Grandparents, uncle, aunt First cousin Second cousin 1 1/2 1/4 1/8 1/32 Genes in common —— I II III ½ ¼ ¼ /8 1 Neural tube defect Incidence 1/1,000 live births Due to failure of closure of brain or spinal cord in foetal life Symptoms may vary with size, location and nature of defect Generally about 3% of recurrent risk FP during pregnancy To reduce chance of occurrence – by giving folic acid to woman before and early pregnancy Encephalocele Meningocele Meningo-myelocele Hydrocephalus Cleft lip & palate Cleft lip & palate Incidence 1/600 to 700 births Due to failure of fusion of 3 upper lip parts to form one continuous lip & closure of the opening in roof of mouth, the latter causing cleft palate Gives rise to feeding problem, teeth development, speech defect & frequent ear infection Risk of recurrence: 1. In unilateral cleft lip – 2.7% In bilateral cleft lip – 5.4% 2. When father affected – 3% of offspring When mother affected – 14% of offspring When one sib affected – 4% of future sibling When two sibs affected – 10% of future sibling Coronary Heart Disease (1) 1. 2. The major cause of morbidity and mortality Genetic factors: Lipid metabolism (a) Familial hypercholesterolaemia (A.D.) 1/500 population; due to defect in LDL receptors on surface of cells (b) Familiam combined hyperlipidaemia (A.D.) 1/200 population; associated with triglyceride & cholesterol Lipoprotein – involved in transport of lipid (a) Apolipoprotein E It binds with LDL receptors on cell surface and responds for cholesterol uptake Coronary Heart Disease (2) (b) Lipoprotein A A glycoprotein & binds apolipoprotein B; highly polymorphic (c) Angiotensin I converting enzyme It converts angiotensin I into II; inactivates bradykinin Environmental factors: diabetes mellitus, hypertension, obesity, smoking, exercise, dietary, menopausal women Diabetes Mellitus Incidence – Year 2000 – 1,700 million world population – Year 2030 – 3,700 million world population – In Hong Kong – 1 in 10 adults, tendency to be younger in type II Maternal diabetes will cause “caudal dysplasia syndrome” in offspring (16% cases) Major features in type I & type II DM > 40 years Insulin production Type I DM (insulin dependent) < 40 years old (HLADR3 or DR4 antigens) None Insulin resistance - + Auto-immunity + - Sibs recurrence 1-6% 10-15% M-Z twin concordance 0.35-0.5 0.9 Obesity Uncommon Common, with family history Onset Type II DM partial Cancers Second leading cause of death, following heart diseases Some cancers may run in family e.g. colon, breast, ovarian, prostate & retinoblastoma “Oncogene” – a gene affecting cell growth or development which can cause cancer “Carcinogen” – cancer-causing agents e.g. – aflatoxin B1 – can induce specific p53 mutation in liver cancer – Benzopyrene – in cigarettes; produces p53 codon mutation in lung cancer (i) Colo-rectal cancer Risk of this cancer with one affected first degree relative is 2x or 3x higher than in general population a) Adenomatous polyposis coli (APC, familial polyposes) a tumour suppressor gene, at 5q21 deletion, related to 85% of C-R cancer, due to mutation b) Hereditary nonpolyposis colon cancer (HNPCC) genes in DNA mis-match repair, at 2q15-21, related to 1-5% of C-R cancer, due to genomic instability Periodic screening of family members on polyps; sigmoidoscopy is advisable (ii) Breast cancer Most common cancer among females When one affected first-degree relative, the risk of developing breast cancer doubles Several gene mutations are known in DNA repair e.g. BRCA1 at 17q21 and BRCA2 at 13q12 However, >90% breast cancers are not hereditary Environmental factors – nulliparity, high fat diet, alcohol, oestrogen replacement therapy Frequent screening by mammography is useful (iii) Ovarian cancer About 5% of females with ovarian cancer have a family history of this disorder Incidence 1/70 women Mutation gene of BRCA1 at 17q21 1% is autosomal dominant gene (iv) Prostate cancer Most common diagnosed cancer in males Second to lung cancer causing death Identified linked polymorphism on 1q When an affected first degree relative, the risk increases by 2 to 3x About 5-10% of prostate cancer are result of inherited mutation Environmental factor - a high-fat diet Readily diagnosed by digital examination and PSA (prostatic specific antigen) test Tumour progresses slowly thus early diagnosis is useful (v) Retinoblastoma Most common childhood eye tumour Incidence 1 in 20,000 40% are familial and inherited as autosomal dominant Multifactorial and bilateral involvement Deletion gene at RB1 at 13q14 15% cases will develop osteosarcoma Treatment – radiation, cryotherapy or enucleation (vi) Cancer cytogenetics “Philadelphia chromosome” in chronic myeloid leukaemia (ph1) Reciprocal translocation between chromosome 9 and 22 or t(9;22) Normal 9 Normal 22 der(9) der(22) Schizophrenia Onset at late adolescent or early adult period Incidence 1% A serious psychotic illness, presented by behaviour problem with emotional disorder showing delusion, withdrawal and hallucination Males & females are equally affected No specific genes have been cloned but the gene “SCZD2” at 11q might predispose to schizophrenia & marked familial aggregation has been observed Schizophrenia When one affected parent is diagnosed, the risk for offspring is 8 to 10% (i.e. 10 times higher than general population) If one affected parent and one sib affected, the risk for next child is 14% recurrence Environmental factors – poor socio-economic status, child born in winter season Poorer prognosis occur in early onset of age and in males Several genes for neurotransmitters (serotonin), N-T receptors and neurotransmitter-related enzymes (e.g. monoamine oxidase, tyrosine hydroxylase, & dopamine-hydroxylase) are studied in families, as well as linkage studies with several markers – the result is inconclusive