Genetics Flashcards
Inherited vs genetic
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
Factors that may increase birth defects
- 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
1st degree relatives
- Children
- Siblings
- Parents
2nd degree relatives
- Grandparents
- Aunts/Uncles
- Nieces/Nephews
3rd degree relatives
- First cousins
Penetrance
- A characteristic of a genotype
- Likelihood that a clinical condition will occur when a particular genotype is present.
- Often defined as complete or incomplete
Autosomal recessive
(assume both parents are carriers)
- Recurrence risk of sibling of affected person
- Risk unaffected sibling is a carrier
- 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)

Cosanguinity risks of autosomal recessive
- 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.
Most common inherited cause of intellectual disability and autism
Fragile X syndrome
Spina bifida
(definition)
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.
Spina bifida
(associated symptoms)
- 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
Spina bifida
(Inheritance)
- 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
Factors that may contribute to spina bifida
- 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
Carrier screening recommendations
(all patients)
- Cystic fibrosis
- Spinal muscular atrophy
Carrier screening recommendations
Hemoglobinopathies
- 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
Carrier screening recommendations
Ashkenazi Jewish diseases
- 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
Spinal Muscular Atrophy
- 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
Who should be tested for Fragile X?
- 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
Aneuploidy
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
Trisomy 13
Patau Syndrome
- Incidence
- Associated birth defects
- Prognosis
- 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.
Trisomy 18
Edwards Syndrome
- Incidence
- Associated birth defects
- Prognosis
- 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
Trisomy 21
Downs syndrome
- Incidence/Prevalence
- Associated birth defects
- ~ 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
Trisomy 21
Downs syndrome
- Associated medical conditions (not birth defects)
- Learning and behavior
- 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)
Is trisomy 21/Downs syndrome hereditary?
- 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.
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
Screening vs Diagnostic test in pregnancy
(general distinction)

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
- Pregnancy Associated Plasma Protein A (PAPP-A)
- 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)
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
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
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
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

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