Down syndrome
• Most common trisomy 1:800 in new born • Most common sever mental retardation • Related with advanced maternal age
Down syndrome
Down syndrome
– Responsible for >100 identifiable syndromes – Collectively more common than all of the Mendelian single gene disorders together!
Chromosome Disorders Are A Major Category of Genetic Disease
• Growth and developmental abnormalities • Family history of chromosome abnormalities • Infertility • Pregnancy with “advanced maternal age” (AMA) • Stillbirth/neonatal death
• Infertility/history of pregnancy loss
• Neoplasia
How is a karyotype prepared?
• • • • • Sample: blood, skin, amnio, CVS Cells grown in culture Blocked in metaphase using colchicine Spread on slide and stained Abnormalities detected by number, morphology and banding pattern
(400 bands per haploid karyotype)
Abnormalities of Chromosome Number and Structure
Abnormalities of Chromosome Number
• Heteroploid
– Any chromosome number other than 46
– Mole: from the Latin mola, for false conception
• Extra maternal set: early spontaneous abortions (SABs)
Molar pregnancies
• Partial mole: remnants of fetal tissue (embryonic and/or extraembryonic) • Triploid, paternal • Complete mole: no fetal tissues • Risk for ovarian teratoma or choriocarcinoma • Diploid but all chromosomes are maternal or paternal, respectively
Interphase & Metaphase Nuclei Giemsa Staining (G-banding)
Normal Human Male Karyotype
Individual Chromosomes Cut from Metaphase Spread
Ideogram of Human Male G-banded Metaphase Chromosomes
Trisomy 13
Trisomy 13
Monosomy
• Almost all monosomy for an entire chromosome is lethal • Turner syndrome: 45,X, the only monosomy can be born and survive
Down syndrome:21/21 t
Offsprings
Down syndrome: t
Down syndrome: t
The Tools: Cytogenetic Analysis
Conventional Karyotyping SKY(spectral karyotyping)
Balanced and Unbalanced Translocations
Translocation
• Reciprocal ~
Resulted from breakage of nonhomologous chromosomes, with reciprocal exchange of the broke-off segments
45, XX, rob ( 13q14q)
Balanced translocation in meiosis
High Risk to produce unbalanced offspring
Translocation Down Syndrome
• 4% of all Down cases • One chromosome is a Robertsonian translocation • 21q + q of another acrocentric chromosome, usually 14 or 22 • 46,XX,rob(14;21),+21 or 46,XY,rob(14;21),+21
What is FISH?
13 12 p 11.2 11.1 11.1 11.2 12 13 11.2 12 13 14 15 21.1 21.2 21.3 22.1 22. 2 q 22.3 23 24 25 26.1 26.2 26. 3
p
q
13 12 11.2 11.1 11.1 11.2 12 13 14 15 21.1 21.2 21.3 22.1 22. 2 22.3 23 24 25 26.1 26.2 26. 3
– Nearly 1% of live births – Approx 2% of prenatal diagnoses in women >35 yrs old – 50% of all first trimester spontaneous abortions
What are the indications for ordering a chromosome analysis?
Reciprocal Translocation (9;22)
Robertsonian Translocation
• Two acrocentric chromosomes fuse near the centromere region with loss of the short arms, which carry multiple copies of genes for rRNA. • Only 45 chromosomes with balanced karyotype and phenotype
Triploidy
• Most often due to fertilization by two sperm (dispermy) or occasionally a diploid sperm or egg • Partial hydatidiform moles (remnants of placenta ± small atrophic fetus): triploid with extra paternal set
Trisomu syndrome）
• 1:20,000 in liveborn and more common in abortion and stillbirth • Severe structural anomalies lead to death in one month
• Significant role in pathogenesis of malignancy
Chromosome Disorders Are A Major Category of Genetic Disease
• Specific chromosomal abnormalities are:
Chromosomal Disorders
Chromosome Disorders Are A Major Category of Genetic Disease
• Large proportion of:
– Reproductive wastage (miscarriages) – Congenital malformations – Mental retardation
Chromosome Anatomy
• • • • • Centromere placement p (short arm) q (long arm) Size Banding pattern (Giemsa stain)
– Heterochromatin (inactive, condensed) - dark – Euchromatin (active, decondensed) - light
Aneuploidy
• Trisomy: three copies – 47,XY+21: Down syndrome • Monosomy: one copy – 45,X: Turner syndrome • Nondisjunction: failure of a pair of chromosomes to separate (to disjoin) normally in meiosis I or II
Trisomy 18 （Edward syndrome）
• 1:7500 in liveborn and more common in abortion and stillbirth • Severe mental retardation and multiple structural anomalies