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
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
3
Q
1st degree relatives
A
- Children
- Siblings
- Parents
4
Q
2nd degree relatives
A
- Grandparents
- Aunts/Uncles
- Nieces/Nephews
5
Q
3rd degree relatives
A
- First cousins
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
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)
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.
9
Q
Most common inherited cause of intellectual disability and autism
A
Fragile X syndrome
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.
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
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
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
14
Q
Carrier screening recommendations
(all patients)
A
- Cystic fibrosis
- Spinal muscular atrophy
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)
- If fractionation indicates possible carrier → appropriate DNA testing
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
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
Are most babies with Downs syndrome born to older parents?
* 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
Screening vs Diagnostic test in pregnancy
(general distinction)
27
First trimester screening
* 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
Nuchal translucency
* 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
Cyctic hygroma
* 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
Nasal bone
* 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
Quad Screen
* 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
Combined Screens
* 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
Factors that go on a screening requisition
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
Non-chromosomal issues detected by serum screening markers
* _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
False positive rate for most serum screenings
5%
36
Recommended f/u of positive serum screening
* 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
What is cell-free DNA (cfDNA)?
* “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
Cell free DNA/Non-invasive prenatal testing recommendations?
_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
Chorionic Villus Sampling (CVS)
* 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
Amniocentesis
* 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)
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