Genetics in pregnancy Flashcards
most common causes of first trimester losses
- 65% chromosomally abnormal
- autosomal trisomy 54% (most common = trisomy 16)
- 12% monosomy X
Triploidy findings and causes
- growth restriction
- holoprosencephaly
- hypertelorism; micrognathia, eye defects, low set ears
- syndactyly of 3rd and 4th fingers, talipes
- cardiac, renal anomalies, omphalocele
- adrenal hypoplasia
- hypoplastic genitalia (males)
- Phenotype
o 1) Type 1: normal/microcephalic head and large placenta with cystic changes = diandry
o 2) Type 2: IUGR, large head, and small noncystic placenta = digyny
Random aneuploidy due to non-disjunction
Random aneuploidy due to non-disjunction
o Trisomy 21, 18, 13
o Sex chromosome abnormalities (45X, 47XXY, 47XYY)
Examples of structural abnormality of chromosomal abnormalities
Structural abnormality:
o Translocation, inversion, deletions, duplications
o May be inherited or de novo
Trisomy 21
Down Syndrome:
- Cardiac defect (VSD, AVCD), ventriculomegaly, duodenal atresia, hydrops, omphalocele
- Soft signs: short F/H, increased NF, UTD, ICEF, echogenic bowel, CPC, clinodactyly
Trisomy 18
Tri 18: small % are due to translocations between 2 chromosomes
- Overlapping fingers; 5th over 4th; 2nd over 3rd
- 95% due to nondisjunction (47, +18); 3% due to translocations involving chromosome 18
- Sonographic findings:
o Increased NT, micrognathia, CPC, ONTD, microcephaly, CHD, CDH, rockerbottom feet, IUGR, echogenic bowel, renal anomalies
- Survival: 63% IUFD; 60% die in 1st week 5% alive at 1 year of age – oldest known survivor 24 yo
- Wilms tumor can complicate survivors
Trisomy 13
Tri 13: 80% secondary to random non-disjunction (47,+13); associated with AMA
- up to 20% have translocation tri 13 (46 XX t(13q14q)
o Much higher % than seen with Down syndrome
- Sonographic findings:
o Holoprosencephaly, increased NT, IUGR, CHD (HLHS), omphalocele, rocker bottom feet, echogenic bowel
- Median survival 3 months; oldest survivor 11 years old
Turner syndrome
Turner:
- Increased neck folds
- Primary amenorrhea, abnormal breast, short stature, high arched palate, webbed neck, short neck, low hairline, multiple nevi
- Hand and pedal edema
- Most common anomaly: cubitous valgus; then short metacarpal, then auditory anomaly, then lymphedema, then hypertension,
o 16% have cardiac anomaly
Turner syndrome
Turner:
- Increased neck folds
- Primary amenorrhea, abnormal breast, short stature, high arched palate, webbed neck, short neck, low hairline, multiple nevi
- Hand and pedal edema
- Most common anomaly: cubitous valgus; then short metacarpal, then auditory anomaly, then lymphedema, then hypertension,
o 16% have cardiac anomaly
DiGeorge syndrome
o Detection is possible by FISH or CGH
o 22q11 deletion:
DiGeorge, Velocardiofacial, Shprintzen syndrome
* Clinical features: CHD, palatal abnormalities, hypocalcemia, immune deficiency
* Will be missed on a karyotype (very small deletion)
* When doing FISH, you have to know what mutation you’re looking for
* Inheritance: 94% of cases are de novo
o Low recurrence risk
o 6% are inherited
50% risk to offspring of affected parent
Afrocentric chromsomes
o Acrocentric chrom: 13, 14, 15, 21, 22: chromosome has 1 large arm and 1 short arm
Robertsonian translocation
- Robertsonian translocation: fusion of 2 acrocentric chromosomes
o Acrocentric chrom: 13, 14, 15, 21, 22: chromosome has 1 large arm and 1 short arm
o Example:
Nonhomologous (majority): 13;14 and 14;21 - 2 different acrocentric chromosomes
- increased risk for miscarriage, T21, T13, uniparental disomy
Homologous (rare): 21;21 (same chromosome) - Miscarriage (no balanced gametes possible)
- If 13;13 rob trans = trisomy 13
- If 21;21 rob trans = trisomy 21
o 14/21 translocation carrier: 45XX, -14,-21, t(14q 21q) – problem is when they procreate
Carrier screening for Ashkenazi Jewish population
- carrier screening available for:
o Tay Sachs
o Canavans
o CF
o Familial Dysautonomia
Serum screening levels for T21, T18, T13
Types of single-gene (Mendelian) inheritance
- Autosomal Dominant
- Autosomal recessive
- X linked
- Duplication and deletion syndromes
- Mitochondrial
- Polygenic/multifactorial
Autosomal dominant characteristics
- Some disease only require a change in 1 of 2 copies of a gene to show a problem
- Conditions either arise brand new or are passed from affected parent to 50% of children
- Inherited by either sex
- Phenotype is determined by:
o Penetrance: incomplete penetrance appears to “skip” generations (eg. BRCA 1)
o Expressivity: degree a gene is expressed, range of phenotype (neurofibromatosis) - All generations, men and women affected
Autosomal recessive
- Chance of having affected child is ¼
- 2/3 of unaffected children are carriers
- Consanguineous couples (related
- May vary by population – 1/12 AA carry a single copy of sickle cell; most prevalent condition
o CF is more common in European Caucasian
o Alpha thal is more common in those from southeast asia
X-linked inheritance
- Comes from altered genes on the X chromosome (usually recessive)
- A change in 1 X can be covered up by information from the other X chromosome in women
- Men have an X and Y – the Y cannot cover up changes of the X because it is different and very small
- Condition passed from a carrier mother (who is fine ) to 50% of her sons, who have the condition
- X linked dominant conditions affect female and are generally lethal in males
o Examples: color blind, muscular dystrophy (CAG), Fragile X MR, hemophilia A and B, Huntington (CAG), Kennedy disease, spinomuscular atrophy (CAG) - Hereditary Unstable DNA:
o Occurs from the presence within a gene or in its promoter region of repeated groups of specific trinucleotides (CAG, CGG , CTG)
o Up to certain number of repeats are normal
o Repeats can expand in male or female meiosis
o Expanded repeats lead to gene abnormality
o Anticipation: gene may become methylated and turned off
Condition worsesnt or occurs early with each subsequent generation
o Some repeats (Fragile X) only expand during female meisosis
o Some repeats (Huntingtons disease) only expand during male meisosis
o Fragile X: most common inherited form of intellectual disability
Occurs in 1:3600 mnales
Transmitted as X linked disorder
Expansion of CGG
Altered transcription of fragile X mental regradation1 gene (FMR1)
Tay Sachs
- Tay Sachs: Hexosaminidase A deficiency
o Carrier frequency 1/30
o Testing method: enzyme or leukocyte assay (for pregnant patients)
Canavans
- Canavans: carrier frequency 1/40
o Testing: DNA mutation assay
Cystic fibrosis
- Cystic fibrosis: abnormal chloride metabolism causes dehydrated secretions; thick mucous in lungs, pancreas, high sweat chloride
o Related to 1300 mutations in CF transmembrane conductance regulator on chromosome 7 (CFTR)
o Diagnosis: 6-8months; 10-20% present with meconium ileus
o Severe recurrent pulmonary infections
o Males are infertile with congenital bilateral absence of the vas deferens
o Median survival: 30 years; PFTs most predictive of outcome
o Treatment: pancreatic enzymes, high fat/high carb diet; chest percussion, antibiotics
o Diagnosis: sweat chloride > 60meq/l x 2; DNA mutation testing
Most common mutation is deltaF508 (70% of cases)
o If screen negative, risk of being carrier reduced (1:29 1/141)
o If father is of high risk group, risk to fetus is 1/116 of being affected (justifies amnio)
Spinal muscular atrophy
- Spinal muscular atrophy (SMA1)
o Autosomal recessive; progressive motor weakness of degeneration and loss of anterior horn cells (lower motor neurons) in the spinal cord and brain stem
o Genes: SMN1 and SMN2
95% are homozygous for deletions of exons 7 and 8 of SMN1
4-5% have 1 deletion on one chromosome and a point mutation on the other
o Carrier frequency: 1/41
Effects of advanced maternal age on aneuploidy (DNA-wise)
Advanced maternal age:
- Related to increased risk for maternal meiosis I ierrors
o 95% DS in general are maternal meiosis 1 errors
o All chromosome disorders which show an increase in frequency with AMA are meiosis I errors
- Meiosis I: arrested in prophase I (dichtyotene) in oocyte development at 5 months embryonic age
o Meiosis I completed at ovulation
o Meiosis II completed at fertilization
o Meiosis I involves pairing and crossing over fo 2 chromatids of homologous chromosomes
Crossing over is necessary for subsequent separation of homologues
1 crossover/telomere
o Nondysjunction associated with decreased number of crossovers; aging affects function of spindle apparatus of the oocyte
- Twin pregnancies: higher risk because of 2 gestational events
o risk equivalent to that of women age 35 carrying twin at age 33
o any chromosomal anomaly : 1/176
Comparison of CVS and amnio
