Genetics in pregnancy

Question 1

most common causes of first trimester losses

Answer 1

• 65% chromosomally abnormal
• autosomal trisomy 54% (most common = trisomy 16)
• 12% monosomy X

Question 2

Triploidy findings and causes

Answer 2

• 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

Question 3

Random aneuploidy due to non-disjunction

Answer 3

Random aneuploidy due to non-disjunction
o Trisomy 21, 18, 13
o Sex chromosome abnormalities (45X, 47XXY, 47XYY)

Question 4

Examples of structural abnormality of chromosomal abnormalities

Answer 4

Structural abnormality:
o Translocation, inversion, deletions, duplications
o May be inherited or de novo

Question 5

Trisomy 21

Answer 5

Down Syndrome:
- Cardiac defect (VSD, AVCD), ventriculomegaly, duodenal atresia, hydrops, omphalocele
- Soft signs: short F/H, increased NF, UTD, ICEF, echogenic bowel, CPC, clinodactyly

Question 6

Trisomy 18

Answer 6

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

Question 7

Trisomy 13

Answer 7

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

Question 8

Turner syndrome

Answer 8

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

Question 9

Turner syndrome

Answer 9

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

Question 10

DiGeorge syndrome

Answer 10

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

Question 11

Afrocentric chromsomes

Answer 11

o Acrocentric chrom: 13, 14, 15, 21, 22: chromosome has 1 large arm and 1 short arm

Question 12

Robertsonian translocation

Answer 12

• 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

Question 13

Carrier screening for Ashkenazi Jewish population

Answer 13

• carrier screening available for:
  o Tay Sachs
  o Canavans
  o CF
  o Familial Dysautonomia

Question 14

Serum screening levels for T21, T18, T13

Answer 14

Question 15

Types of single-gene (Mendelian) inheritance

Answer 15

• Autosomal Dominant
• Autosomal recessive
• X linked
• Duplication and deletion syndromes
• Mitochondrial
• Polygenic/multifactorial

Question 16

Autosomal dominant characteristics

Answer 16

• 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

Question 17

Autosomal recessive

Answer 17

• 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

Question 18

X-linked inheritance

Answer 18

• 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)

Question 19

Tay Sachs

Answer 19

• Tay Sachs: Hexosaminidase A deficiency
  o Carrier frequency 1/30
  o Testing method: enzyme or leukocyte assay (for pregnant patients)

Question 20

Canavans

Answer 20

• Canavans: carrier frequency 1/40
  o Testing: DNA mutation assay

Question 21

Cystic fibrosis

Answer 21

• 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)

Question 22

Spinal muscular atrophy

Answer 22

• 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

Question 23

Effects of advanced maternal age on aneuploidy (DNA-wise)

Answer 23

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

Question 24

Comparison of CVS and amnio

Answer 24