Clinicalcytogenetics.ppt

1、Clinical cytogenetics,Disorders of the autosomes and the sex chromosomes,Outline,First discuss the most common autosomal disorders; Second discuss the unique biology of X and Y chromosomes and sex chromosome abnormalities. Third discuss disorders of gonadal development and sexual differentiation,Aut

2、osomal disorders,Trisomy 21 (Down syndrome) Trisomy 18 (Edwards Syndrome) Trisomy 13 (Patau Syndrome,Common phenotype,Growth retardation Mental retardation Multiple congenital anomalies,Down syndrome,Or trisomy 21,is the most common chromosome disorders and is the most common genetic cause of modera

3、te mental retardation. About 1 in 800 is born with Down syndrome,Was first described clinically by Langdon Down in 1866. Down syndrome was the first conditions to be found to have 47 chromosomes,with an extra chromosome 21,Mother age and incidence of Down syndrome,Phenotype,The chromosomes in Down s

4、yndrome,Trisomy 21 Robertsonian translocation Mosaic Down syndrome,Trisomy 21,In about 95% of all patients Resulting from meiotic nondisjunction 90% meiotic error responsible for the trisomy usually occurs during maternal meiosis. 10% occur in paternal meiosis. The risk increases with maternal age,D

5、own Syndrome 47,XY,+21,Examples: (1) Downs Syndrome trisomy 21 1 out of 800 children,Robertsonian translocation,In about 4% of Down syndrome patients, The karyotype is 46,XX(XY),rob(14;21),+21 or 46,XX(XY),rob(G;21),+21, Shows no relation to maternal age,but has a high frequency risk in families whe

6、n a parent is a carrier of the translocation,Consequences of balanced Robertsonian translocation,21q21q Translocation,Is a chromosome comprising two chromosome 21 long arms. Originate as an isochromosome. A carrier is probably to have only children with Down syndrome,Karyotype of 21q21q translocatio

7、n,Mosaic Down syndrome,The karyotype is 46,XX/47,XX,+21 or 46,XY/47,XY,+21 The phenotype may be milder than that of typical trisomy,Partial trisomy 21,A patient in whom only a part of the long arm of chromosome 21 is present in triplicate,Etiology of trisomy 21,The “older egg” model:the older the oo

8、cyte,the greater the chance that the chromosomes will fail to disjoin correctly,Risk of Down syndrome,The population incidence in live birth is about 1 in 800, The risk of typical trisomy-21 reaching 1 in 25 births in the oldest maternal age group. However,more than half of the mothers of all Down s

9、yndrome babies are younger than 35 years. The risk of Down syndrome due to translocation or partial trisomy is unrelated to maternal age,Recurrence risk,The recurrence risk of trisomy 21 is about 1% overall. For mothers younger than 30 years,the risk is about 1.4%, For older mothers it is the same a

10、s the age-related risk. The recurrence risk for down syndrome due to translocation is much higher,Trisomy 18,Edward Syndrome 47,XX,+18,The incidence in liveborn is about 1 in 7500 births. 95% of trisomy 18 conceptuses are aborted spontaneously. It is rare for babies to survive for a few months if li

11、veborn because of the multitude of anomalies that are usually present,About 80% of the patients are female. Increased maternal age is an influential factor. The karyotype can be Trisomy 18 Robertsonian translocation Mosaic,Trisomy 13,Phenotype,Growth retardation Severe mental retardation Severe nerv

12、ous system malformation Sloping forehead Open sutures Absence of the eyes or one eye Cleft lip or cleft palate malformed ears Polydactyly hands or feet Hands clench Rocker bottom appearance feet,The incidence in livebirth is about 1 in 20,000 to 25,000 births. It is associated with increased materna

13、l age. Extra chromosome usually arises from nondisjunction in maternal meiosis I. The karyotype can be Trisomy 13 Robertsonian translocation Mosaic,Cri Du Chat syndrome,Appearance,1/50,000 births Mental retardation Slow motor skill development Low birth weight and slow growth Small head (microcephal

14、y) Partial webbing of fingers or toes Wide-set eyes (hypertelorism) High-pitched cry,Cri du Chat 5p,Cri Du Chat syndrome,5p15,10% to 15% of the patients are the offspring of translocation carriers. The critical deleted region has been identified as band 5p15. Many of the clinical findings appear to

15、be due to haploinsufficiency of genes within band 5p15.2,and distinctive cat cry appears to result from deletion of 5p15.3,Microdeletion syndrome,Several dysmorphic syndromes are associated with small,but sometimes cytogenetically visible,deletions,leading to a form of genetic imbalance referred to

16、as segmental aneusomy.These deletion produce syndromes that are usually clinically recognizable and that can be detected either by high-resolution chromosome analysis or by FISH,Cytogenetic abnormalities of the sex chromosomes,Numerical (1/400-1/500) Structural- X,i(Xq) (15%) Mosaic,47,XXY(Klinefelt

17、er syndrome,47,XYY,47,XXX(Trisomy X,45,X(Turner syndrome,Observation on patients with sex chromosome aneuploidy,Common features,Delay in onset of puberty Amenorrhea Infertility Ambiguous genitalia,Klinefelter syndrome,Klinefelter Syndrome: 47; XXY frequency about 1/1,000 male births taller than norm

18、al hypogonadism usually infertile gynecomastia (enlarged breasts in 20% of cases) often show mildly depressed intelligence,karyotype,Several variants of karyotype,46,XY/47,XXY (15%) 48,XXYY 48,XXXY 49,XXXXY,Mechanism,47,XYY syndrome,The incidence is about 1 in 1000. Often havent obvious phenotype. T

19、all,(2/36 feet tall) normally fertile with offspring of normal karyotype. Was associated with violent behavior. Slightly depressed intelligence,Several variants,48,XXYY 49,XXXYY,Mechanism,Paternal nondisjunction at meiosis,producing YY sperm. Variants originate in the father as a result of sequentia

20、l nondisjunction in meiosisand meiosis,Trisomy X syndome,Karyotype,47,XXX syndrome,The incidence is about 1 in 1000 female births. Often havent obvious phenotype. They are usually fertile. Slightly depressed intelligence. Two of the X chromosomes are inactivated,Several variants,48,XXXX 49,XXXXX,Mechanism,Result from errors in maternal meiosis . The increased maternal age is relation to the risk,Turner syndrome,Phenotype,