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Genetic Basis of Pregnancy
Chromosome abnormalities during pregnancy
Origin: gametogenesis, fertilization, post-zygotic cleavage
Consequences: preimplantation death, implantation failure, SAB
Classes of chromosome aberrations (CA)
Aneuploidy
Polyploidy
Structural rearrangements
Aneuploidy during pregnancy Aneuploid oocytes: 15-30% 2. Aneuploid spermatozoa: 3%
Fertilization-related CAs: 8%
Aneuploid preimplantation embryos: 24%
Aneuploid first trimester embryos: 15-25% 6. Aneuploid 2nd and 3rd trimester fetuses: 7% 7. Aneuploid newborns: 0.3-0.5%
Structural congenital malformations: 4%
Mental retardation: 12%
Congenital heart defects: 13%
Types of CAs during pregnancy
Aneuploidy
45, X: 28%
Trisomy 16: 31%
Trisomy 18: 5%
Trisomy 21: 8%
Trisomy 22: 10%
down syndrome, downs
Structural rearrangements: 5.1%
Risk of trisomy conception following abortion of unknown karyotype
Risk of subsequent trisomy abortion: 4.5%
Risk of subsequent trisomic liveborn: 0.45%
Risk of trisomic offspring subsequent to trisomic abortion: 0.5%
II. Chromosome Aberrations as a Cause of Congenital Malformations
A. Autosomal chromosome aberrations
1. Trisomy 21 (Down)
a. Incidence: 1 in 600-800 live births
b. Risk increases with advancing maternal age
c. Mechanism of origin: nondisjunction and nontranslocation
d. Clinical findings: hypotonia, characteristic facies, cardiac malformations, duodenal atresia e. Recurrence risks
1) In trisomic Down syndrome
2) In translocation Down syndrome
2. Trisomy 13
a. Incidence: 1/2,000-4,000 live births
b. Clinical findings: cleft lip and/or cleft palate, microphthalmia, polydactyly, parietal scalp lesions, cardiac and renal anomalies.
3. Trisomy 18
a. Incidence: 1/2,000-4,000 live births
b. Clinical findings: SGA, hypertonia, contractures, characteristic facies, short rib cage, overlapping 1st and 5th fingers, rocker-bottom feet, dorsiflexion of hallux
B. Sex chromosome aberrations
1. Gonadal dysgenesis (Turner)
a. Cytogenetic findings: 45,X, mosaicism, isochromosome, and structural abnormalities
b. Clinical findings: short stature, webbed neck, low hairline, shield-like chest, increased carrying angle
2. Syndromes which appear normal during gestation
a. Triplo-X, 47,XXX
b. Kleinfelter, 47,XXY c. YY males
C. Structural rearrangements
1. Translocations: balanced and unbalanced
2. Deletions and duplications: cri-du-chat and 5p-
3. Inversions
D. Uniparental disomy (UD) and imprinting (I)
1. UD: both chromosomes of a pair derived from one parent
2. I: maternal and paternal genes differentially altered during meiosis
3. Clinical implications: Beckwith Weidemann syndrome
A. Pedigree analysis
1. Autosomal dominant: vertical transmission
2. Autosomal recessive: horizontal pattern of familial transmission
3. X-linked: oblique pattern of familial transmission
B. Characteristics of autosomal dominant traits
1. Variable in penetrance and expression due to:
a. Genomic imprinting
b. Anticipation due to unstable DNA: myotonic dystrophy
c. Mosaicism: osteogenesis imperfecta
d. Somatic mutation: familial cancer
C. Characteristics of autosomal recessive traits
1. Risk of being a carrier based on ethnicity:
a. Tay Sachs disease: i in 30 Ashkenazi Jews
b. Sickle cell disease: I in 10 African Americans c. Cystic fibrosis: I in 20 in Caucasians d. Thalassemia: Greek and Italians
2. Carrier testing
a. Tay Sachs disease: hexosaminidase activity levels
b. Sickle cell disease: hemoglobin electrophoresis
c. Cystic fibrosis: DNA testing (up to 64 of >500 mutations)
d. Thalassemia: CBC and MCV profile
3. Prenatal diagnosis available for TSD, SS, CF and thalassemia (alpha, beta)
D. X-linked inheritance
1. Fragile X mental retardation (FHR) syndrome a. Most common genetic form of MR in males b. Atypical pattern of inheritance
1) 20% of male carriers unaffected
2) 50% of female carriers affected
c. Gene defect identified on Xq27
1) Increase in trinucleotide repeats, CGG
2) All males and 50% of females with full mutation (>200 repeats) are mentally retarded
d. Permutation is first step before full mutation
2. Prenatal diagnosis of fragile X
a. Diagnosis now by DNA analysis (not cytogenetics) b. Requires considerable genetic counseling