Genetics

Question 1

Inherited vs genetic

Answer 1

Genetic - medical condition or trait that is related to our genes

Inherited = condition that you may be able to track through a family, or having a family history may predispose you to them

• Mendelian Patterns: Cystic Fibrosis, Tay Sachs Disease
• Multifactorial: Addiction, Alzheimer’s Disease, Schizophrenia, Autism
• Multigenic: Red Hair, Freckles

Many conditions have a genetic component but are new to the person that is affected

• Most types of cancers: Colon Cancer
• Many chromosome conditions: Down Syndrome

Question 2

Factors that may increase birth defects

Answer 2

• Smoking, drinking alcohol, or recreational drug use during pregnancy.
• Maternal medical conditions (e.g. uncontrolled diabetes before and during pregnancy).
• Certain medications, such as isotretinoin (a drug used to treat severe acne).
• Family hx of birth defects.
• Being an older mother, typically age > 35 years

Question 3

1st degree relatives

Answer 3

• Children
• Siblings
• Parents

Question 4

2nd degree relatives

Answer 4

• Grandparents
• Aunts/Uncles
• Nieces/Nephews

Question 5

3rd degree relatives

Answer 5

• First cousins

Question 6

Penetrance

Answer 6

• A characteristic of a genotype
• Likelihood that a clinical condition will occur when a particular genotype is present.
• Often defined as complete or incomplete

Question 7

Autosomal recessive

(assume both parents are carriers)

• Recurrence risk of sibling of affected person
• Risk unaffected sibling is a carrier

Answer 7

• Recurrence risk of sibling of affected person: ¼ (25%)
• Risk unaffected sibling is a carrier: 2/3

(Lecturer said it would be a good test question)

Question 8

Cosanguinity risks of autosomal recessive

Answer 8

• Absolute risks of abnormal offspring (stillbirth, neonatal death, and congenital malformation)
  
  • Couple is 1st cousins: 3-5%
  • Unrelated couple: 2-3%
• Consanguinity at the level of third cousins (or more remote relationships) is not considered to be genetically significant.

Question 9

Most common inherited cause of intellectual disability and autism

Answer 9

Fragile X syndrome

Question 10

Spina bifida

(definition)

Answer 10

Birth defect in which an area of the spinal column does not form properly, leaving a section of the spinal cord and spinal nerves exposed through an opening in the back.

Question 11

Spina bifida

(associated symptoms)

Answer 11

• Bladder and bowel problems
• Sexual dysfunction
• Weakness and loss of sensation below the level of the defect
• Inability to more the lower legs and other cognitive impairments
• Orthopedic malformations such as club feet or problems with the knees or hips

Generally, the higher the defect, the more severe the condition

Question 12

Spina bifida

(Inheritance)

Answer 12

• Majority of cases do not run in families
• Multifactorial condition - happen because of a combination of many different factors
• Rarely able to identify a single factor that causes a baby to have spina bifida
• Recurrence risk for families: 3-4%, reduced to 1% if additional folic acid given prior to conception

Question 13

Factors that may contribute to spina bifida

Answer 13

• Genetic component: many different genes, each playing a small role
• Diabetes
• Medication exposures
• Fever (>102F) or exposure to sauna/jacuzzi in 1st trimester
• Lack of folic acid supplementation

Rarely can find single factor that points to it

Question 14

Carrier screening recommendations

(all patients)

Answer 14

• Cystic fibrosis
• Spinal muscular atrophy

Question 15

Carrier screening recommendations

Hemoglobinopathies

Answer 15

• Ethnicities:
  
  • African
  • Mediterranean
  • Middle Eastern
  • Southeast Asian
  • Hispanic
• Screen by hemoglobin fractionation (electrophoresis) and CBC
  
  • If fractionation indicates possible carrier → appropriate DNA testing
    • β-thalassemia: gene sequencing
    • α-thalassemia: deletion/duplication (and Constant Spring variant)

Question 16

Carrier screening recommendations

Ashkenazi Jewish diseases

Answer 16

• Screening should be offered to:
  
  • Ashkenazi Jewish individuals and their partners
  • Individuals with at least one AJ grandparent
  • Any individual with a significant family history
  • Ashkenazi Jewish gamete donors
  • Preconception screening is ideal
• 1 in 4 Jews is a carrier for at least 1 of 19 preventable Jewish genetic diseases
• 1 in 24 CF carrier
• Tay Sachs - destroys nerve cells in brain + spinal cord

Question 17

Spinal Muscular Atrophy

Answer 17

• Most common genetic cause of childhood mortality
  
  • 60–70% die by age 2 for most common type
• Deletion of the Survival Motor Neuron 1 gene (SMN1) → degeneration of lower motor neurons → progressive muscle weakness
• Variability of severity and age of onset
• Autosomal recessive inheritance
• Second-most common inherited disorder
• Incidence is 1/6,000–1/10,000
• • Carrier frequency is ~1/40
• SMA carrier screening looks at SMN1 copy number of unaffected individuals

Question 18

Who should be tested for Fragile X?

Answer 18

• Family history of Fragile X-related disorders
  
  • Intellectual disability, developmental delay, autism, premature ovarian insufficiency
• Personal history of POI or elevated FSH
• People who request carrier screening

Question 19

Aneuploidy

Answer 19

Changes in the Numbers of Chromosomes

Most common genetic cause of miscarriage and birth defects

• Trisomy: One extra copy of a single chromosome
  
  • Example: Trisomy 21 - Down Syndrome
• Monosomy: One missing copy of a single chromosome
  
  • Example: Turner Syndrome - 45,X (only monosomy compatible with life)
• Triploidy - Three copies of every chromosome

Question 20

Trisomy 13

Patau Syndrome

• Incidence
• Associated birth defects
• Prognosis

Answer 20

• 1 in 16,000 newborns (more common in pregnancy, but many dont survive to term)
• Associated birth defects:
  
  • Brain or spinal cord anomalies
  • Small or poorly developed eyes (microphthalmia)
  • Extra fingers or toes
  • Congenital heart defects
  • Cleft lip/cleft palate
  • Weak muscle tone (hypotonia)
  • Severe intellectual disability
  • Seizures
• Poor prognosis
  
  • 44% will die within the first month of life
  • 69% will die within the first 6 months of life
  • 5-10% percent of children with this condition live past their first year.

Question 21

Trisomy 18

Edwards Syndrome

• Incidence
• Associated birth defects
• Prognosis

Answer 21

• 1 in 5,000 newborns (more common in pregnancy but many don’t survive to term)
• Associated birth defects:
  
  • IUGR and LBW
  • Small head with abnormal shape, small jaw and mouth
  • Choroid plexus cysts
  • Congenital heart defects
  • Clenched hands with overlapping fingers
  • Rocker Bottom Feet
  • Failure to Thrive
• Poor Prognosis
  
  • 30% will die within the 1st month of life
  • 50% will die within the 1st 2 months of life
  • 5-10% of children with this condition live past their 1st year, and these children often have severe intellectual disability

Question 22

Trisomy 21

Downs syndrome

• Incidence/Prevalence
• Associated birth defects

Answer 22

• ~ 1 in 700 newborns
• Approximately 200,000 people in the US have Down syndrome
• Associated birth defects:
  
  • Congenital heart defects (approximately 50%)
  • Duodenal Atresia
  • Soft Signs: Absent/short nasal bone, enlarged kidneys, shortened long bones, fifth finger clinodactyly
  • Characteristic facial features

Question 23

Trisomy 21

Downs syndrome

• Associated medical conditions (not birth defects)
• Learning and behavior

Answer 23

• Associated medical conditions:
  
  • Gastroesophageal reflex
  • Celiac disease
  • Hypothyroidism (seen in approximately 15%)
  • Increased risk of hearing and vision problems
  • Increased risk for leukemia
  • Increased risk for Alzheimer disease (seen in approximately 50% of adults with Down syndrome, with onset in fifties to sixties)
• Learning and Behavior
  
  • Mild to moderate intellectual disability
  • Delayed speech and language
  • Attention problems, obsessive/compulsive behavior, stubbornness or tantrums
  • Autism spectrum disorders (in a small percentage)

Question 24

Is trisomy 21/Downs syndrome hereditary?

Answer 24

• Rarely (1%)
• Translocation, a type of Down syndrome that accounts for 3 to 4% of all cases, is the only type of Down syndrome known to have a hereditary component. Of those, one third (or 1% of all cases of Down syndrome) are hereditary.

Question 25

Are most babies with Downs syndrome born to older parents?

Answer 25

• No
• Most are born to people younger than 35 years old simply because younger people have more children.
• But the likelihood of having a child with Down syndrome increases with the age of the mother, especially after age 35

Question 26

Screening vs Diagnostic test in pregnancy

(general distinction)

Answer 26

Question 27

First trimester screening

Answer 27

• Blood tests:
  
  • Pregnancy Associated Plasma Protein A (PAPP-A)
    
    • Produced by the placenta
    • Decreased in pregnancies at risk for chromosomal conditions
  • Human chorionic gonadotrophin (hCG)
    
    • Produced by the placenta
    • Increased in pregnancies at risk for Down Syndrome
• Ultrasound evaluation
  
  • Performed between 11-14 weeks gestation
  • Crown-Rump Length: measurement of baby from head to bottom to get an accurate measurement of gestational age
  • Nuchal translucency
  • Nasal bone (some locations)

Question 28

Nuchal translucency

Answer 28

• Pocket of fluid at the back of baby’s neck
• Normal variant up to 2.5-3.0 mm (depends on gestational age)
• Greater than 2.5-3.0 – increased risk for chromosomal abnormalities, skeletal dysplasias, heart defects, and other health conditions
• Ultrasonographers must have special training, can limit the availability of FTS in some areas

Question 29

Cyctic hygroma

Answer 29

• Skin thickening extending the entire length of the fetus within the first trimester
• Carries severely increased risk for adverse pregnancy outcomes:
  
  • 50% risk of aneuploidy
  • Of pregnancies that have a normal karyotype, 50% risk of cardiac malformation or another major birth defect
  • Of those that have a normal karyotype and are structurally normal, 25% will have an increased risk for IUFD

Question 30

Nasal bone

Answer 30

• Absence in the 1st trimester can be another indicator of an increased risk for Down Syndrome
• 73% of fetuses with Down Syndrome have no nasal bone
• Can also occur in healthy babies, but much less common (0.5%)
• Can be due to ethnicity – absent nasal bone is higher in those of Asian, African, and Afro-Caribbean populations
• Thought that adding nasal bone to the 1st trimester screen may increase the ability of FTS to identify up to 93% of cases of Down Syndrome
• May also be a sign for other aneuploidies such as Trisomy 13, 18, and Turner Syndrome

Question 31

Quad Screen

Answer 31

• Done between 15w0d and 21w6d
• Assesses risk for Down Syndrome, Trisomy 18, and Open Neural Tube Defects
• Blood work only
  
  • Alpha-Fetoprotein (AFP) - made by fetus
  • Unconjugated estriol (uE3) - made by fetus
  • Inhibin A - made by fetus
  • hCG – same as FTS, made by placenta
• Able to accurately detect
  
  • 80% of cases of Down Syndrome
  • 70% of cases of Trisomy 18
  • 80% of cases of open NTD

Question 32

Combined Screens

Answer 32

• Sequential Screen
  
  • FTS is done, and second test may follow
  • If risk is very high for Down Syndrome (>1 in 45) or Trisomy 18 (>1 in 100), then result is called out, and second part of test is not done
  • If risk is lower than those risks above, second set of blood work is done, and a final risk is reported
  • Able to identify
    
    • 92.3% of cases of Down Syndrome
    • 90% of cases of Trisomy 18
    • 80% of cases of ONTD
• Integrated Screen
  
  • Combines both FTS and Quad screen, no result is reported until second trimester (risks are not calculated after the first blood draw)
  • Able to identify
    
    • 92.4% of cases of Down Syndrome
    • 90% of cases of Trisomy 18
    • 80% of cases of ONTD

Question 33

Factors that go on a screening requisition

Answer 33

1. Age of patient: Age provides us with the baseline risk for chromosomal abnormalities to compare result to
2. Gestational age of fetus: The different chemicals assessed by maternal serum screening vary depending on gestational age
3. If mother has diabetes: Women who are diabetic have lower levels of AFP, but higher levels of ONTD compared to women without diabetes
4. Mother’s ethnicity: African-American women have higher levels of AFP, but lower levels of ONTD compared to women who are not African-American
5. Maternal Weight: Maternal Serum markers are adjusted depending on a patient’s weight
6. Singleton or Multiple Gestation: Values will change based on the number of babies

Question 34

Non-chromosomal issues detected by serum screening markers

Answer 34

• Abdominal Wall Defects like Omphalocele and Gastroschisis → Elevated AFP
• Smith Lemli Opitz Syndrome or steroid sulfatase deficiencies → Decreased uE3
• I_ncreased risk for congenital nephrotic syndrome or Incontininenti Pigmenti_ → Extremely Elevated AFP
• OB complications (FGR, SAB, PEC, abruption, preterm delivery) → PAPP-A < 5th percentile in 1st tri
• Increased risk of IUFD, FGR PEC (in pregnancies w/o structural anomalies) → Elevated hCG, AFP, DIA in 2nd tri
• Risk of adverse outcome increases with # of abnormal markers and with more extreme values
• No evidence-based management strategies

Question 35

False positive rate for most serum screenings

Answer 35

5%

Question 36

Recommended f/u of positive serum screening

Answer 36

• Further detailed counseling
• Cell-free DNA screening for patients who want to avoid a diagnostic test
  
  • Counsel that false negative = about 2%
  • May delay definitive dx and management.
• CVS or amniocentesis.
• Evaluation for fetal anomalies by 2nd tri U/S is appropriate for all patients.
• Other considerations:
• Simultaneous testing with multiple screening methodologies for aneuploidy should NOT be performed.
• Negative screening test result → don’t offer additional screening for aneuploidy → increase potential for false positive.

Question 37

What is cell-free DNA (cfDNA)?

Answer 37

• “Fetal DNA” released into parent bloodstream as small fragments (150–200bp)
• Parental blood contains both placental and parental cfDNA
• 2–20% of total cfDNA is fetal/placental in origin
• Fetal cfDNA reliably detected after 10+ weeks gestation
• Undetectable within hours postpartum
• Massively parallel sequencing (next generation) - uses millions of probes to amplify/sort the unique DNA fragments based on what chromosome they belong to
  
  • Screened for mutations and counted to help determine if there is too much or too little DNA (aneuploidy)
  • Entire genome is covered → high sensitivity and specificity for aneuploidy (esp T18/T21)

Question 38

Cell free DNA/Non-invasive prenatal testing recommendations?

Answer 38

ACOG/SMFM

• Appropriate for everyone, tho low-risk pts still get conventional screening
• non-reportable cfDNA result are at increased risk for aneuploidy → offer diagnostic testing
• cfDNA screening should not routinely be used for microdeletion syndromes or in multiple gestations

ACGM recommendations

• NIPT can replace conventional screening for T21/13/18 across the parental age spectrum, for a continuum of gestational age beginning at 9–10 weeks, and for patients who are not significantly obese.
• Patients can select diagnostic or screening approaches for consistent with their personal goals and preferences.
• Informing all pregnant patients that diagnostic testing (CVS or amniocentesis) is an option for the detection of chromosome abnormalities and clinically significant CNVs.

Question 39

Chorionic Villus Sampling (CVS)

Answer 39

• Diagnostic test that collects a sample of the placenta
• Baby and placenta are made of the same type of tissue
• Can be done transvaginally or transabdominally
• Routinely done between 10 and 12 weeks gestation
• Risk is 1 in 100, or 1%, for a complication**
• Small risk (1%) that cells in placenta may be different that cells in the baby: confined placental mosaicism

Question 40

Amniocentesis

Answer 40

• Procedure used to collect a sample of amniotic fluid from around the baby
• Fluid contains baby’s skin cells and cells from the kidney/bladder
• Typically performed after 15 weeks gestation
• Risk is approximately 1 in 200, or 0.5%**
• Most accurate way to get genetic information about the baby before birth