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Fetal Evaluation (UPenn) > Genetics > Flashcards

Genetics Flashcards

1
Q

Inherited vs genetic

A

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
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2
Q

Factors that may increase birth defects

A
  • 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
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3
Q

1st degree relatives

A
  • Children
  • Siblings
  • Parents
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4
Q

2nd degree relatives

A
  • Grandparents
  • Aunts/Uncles
  • Nieces/Nephews
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5
Q

3rd degree relatives

A
  • First cousins
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6
Q

Penetrance

A
  • A characteristic of a genotype
  • Likelihood that a clinical condition will occur when a particular genotype is present.
  • Often defined as complete or incomplete
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7
Q

Autosomal recessive

(assume both parents are carriers)

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

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8
Q

Cosanguinity risks of autosomal recessive

A
  • 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.
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9
Q

Most common inherited cause of intellectual disability and autism

A

Fragile X syndrome

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10
Q

Spina bifida

(definition)

A

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.

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11
Q

Spina bifida

(associated symptoms)

A
  • 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

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12
Q

Spina bifida

(Inheritance)

A
  • 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
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13
Q

Factors that may contribute to spina bifida

A
  • 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

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14
Q

Carrier screening recommendations

(all patients)

A
  • Cystic fibrosis
  • Spinal muscular atrophy
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15
Q

Carrier screening recommendations

Hemoglobinopathies

A
  • 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)
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16
Q

Carrier screening recommendations

Ashkenazi Jewish diseases

A
  • 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
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17
Q

Spinal Muscular Atrophy

A
  • 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
18
Q

Who should be tested for Fragile X?

A
  • 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
19
Q

Aneuploidy

A

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
20
Q

Trisomy 13

Patau Syndrome

  • Incidence
  • Associated birth defects
  • Prognosis
A
  • 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.
21
Q

Trisomy 18

Edwards Syndrome

  • Incidence
  • Associated birth defects
  • Prognosis
A
  • 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
22
Q

Trisomy 21

Downs syndrome

  • Incidence/Prevalence
  • Associated birth defects
A
  • ~ 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
23
Q

Trisomy 21

Downs syndrome

  • Associated medical conditions (not birth defects)
  • Learning and behavior
A
  • 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)
24
Q

Is trisomy 21/Downs syndrome hereditary?

A
  • 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.
25
Q

Are most babies with Downs syndrome born to older parents?

A
  • 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
26
Q

Screening vs Diagnostic test in pregnancy

(general distinction)

A
27
Q

First trimester screening

A
  • 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)
28
Q

Nuchal translucency

A
  • 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
29
Q

Cyctic hygroma

A
  • 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
30
Q

Nasal bone

A
  • 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
31
Q

Quad Screen

A
  • 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
32
Q

Combined Screens

A
  • 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
33
Q

Factors that go on a screening requisition

A
  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
34
Q

Non-chromosomal issues detected by serum screening markers

A
  • 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
35
Q

False positive rate for most serum screenings

A

5%

36
Q

Recommended f/u of positive serum screening

A
  • 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.
37
Q

What is cell-free DNA (cfDNA)?

A
  • “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)
38
Q

Cell free DNA/Non-invasive prenatal testing recommendations?

A

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.
39
Q

Chorionic Villus Sampling (CVS)

A
  • 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
40
Q

Amniocentesis

A
  • 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

Fetal Evaluation (UPenn) (5 decks)

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