Aneuploidies Flashcards
What are the three most common genetic cause of Down Syndrome, and how are they inherited?
Down Syndrome is most commonly caused by maternal meiotic nondisjunction (~90%, typically meiosis I). It is sporadic and associated with advanced maternal age. Other causes include balanced translocations (~5%) and mosaicism (3-5%).
What are the key prenatal screening markers for trisomy 21in the first and second trimester? And what would you expect to see in the event of 21+
First Trimester (Combined Screening):
Free β-hCG is and PAPP-A (Pregnancy-Associated Plasma Protein A) elevated.
Nuchal Translucency (NT) increased
Absent nasal bone (European ancestry )
Second Trimester (Quad Screen):
β-hCG still up along with Inhibin-A and Estriol (uE3)
AFP (Alpha-Fetoprotein) is decreased
When combined with maternal and gestational age, these markers help calculate the risk of Trisomy 21. NIPS has higher sensitivity and specificity.
What are the most common physical characteristics seen in patients with Down Syndrome? What are associated medical and developmental concerns?
1) Facial and physical features:
Flat nasal bridge, epicanthic folds, upslanting palpebral fissures, small low-set ears, short neck, protruding tongue, single palmar crease, sandal gap
2)ID: Cognitive impairment (mild to moderate).
and developmental milestone delay
3)Congenital Heart Defects:
40-50% of individuals. Atrioventricular (AV) canal defect most common. VSD, ASD and ToF possible
4)Endocrine Issues: risk of hypothyroidism.
5)Heme Onc: Increased AML and ALL risk, (megakaryoblastic subtype). Transient abnormal myelopoiesis (TAM) also possible
6)Gastrointestinal Abnormalities:
duodenal atresia (double bubble), Hirschsprung disease & celiac
7)Immune System Dysfunction: Increased susceptibility to infections due to immunodeficiency.
8)Neurologic and Psychiatric : risk of early-onset Alzheimer’s disease (amyloid precursor protein on chr21). ADHD, and ASD traits, sleep disturbances
9)Ophthalmologic Issues: strabismus, cataracts, refractive errors, and keratoconus.
10)Hearing Loss: Conductive or sensorineural hearing loss common
11)Orthopedic Concerns: Hypotonia, atlantoaxial instability (excessive movement between the first and second cervical vertebrae), lax ligament
12)Dental and Oral Health: Delayed tooth eruption and malocclusion
13)Obesity and Metabolic Issues: Higher prevalence of obesity due to hypotonia, lower activity levels, and metabolic factors.
What are the key elements of managing Down Syndrome?
Management is multidisciplinary and includes:
Cardiology: Monitoring and treatment of congenital heart defects.
Endocrinology: Screening and treatment for hypothyroidism.
Developmental therapy: Early intervention, including physical, occupational, and speech therapy.
What are the genetic causes and inheritance patterns of Edwards Syndrome?
Meiotic (maternal) nondisjunction during meiosis II -> extra copy of chromosome 18 associated with AMA
Mosaicism is rare but may result in a milder phenotype.
What are test values are identicative of trisomy 18 in first and second trimester prenatal screening options
NIPS: High sensitivity (above 97%) and specificity (99%) this will present with probability
First-trimester screening: Free β-hCG & PAPP-A are decreased and NT is increased.
Second-trimester quad screen:
AFP, β-hCG, estriol, inhibin-A: All decreased.
Given a positive screen for trisomy 13, 18 or 21, what are a pregnant person’s diagnostic test options and what are the risks?
Chorionic Villus Sampling (CVS):
10–13 weeks, directly analyzes placental tissue, results are available sooner than with amniocentesis.
Risk of pregnancy loss (~1 in 100–200).
Confined placental mosaicism (placental DNA differs from fetal DNA) can happen -> ambiguous results.
Rare risk of collecting maternal cells -> false-negative.
Other risks: Vaginal bleeding, amniotic fluid leakage, infection, and cell culture failure in the lab.
May cause cramping and discomfort.
Amniocentesis:
15+ weeks. Directly examines fetal DNA, eliminating the risk of placental mosaicism or maternal cell contamination. ~1 in 500 risk of miscarriage
Risks include miscarriage (rare), amniotic fluid leakage, vaginal bleeding
Potential for cell culture failure in the lab
What are three lab testing options after a CVS or amnio has been performed from least to most informative, what can each test detect, and what are some + and - of these tests?
Fluorescence In Situ Hybridization (FISH): Detects trisomies (21, 18, 13, X, Y). Results need further confirmation but quick TAT (24–48 hours).
Karyotype Analysis: Examines all chromosomes for numerical and structural abnormalities. Detects balanced translocations. Longer TAT (10–14 days), risk of cell culture failure.
Chromosomal Microarray (CMA): Detects extra/missing genetic material at a smaller scale than karyotyping.
Comprehensive, TAT at 5–7 days and lower failure rate.
May identify VUS, non-paternity, adult conditions
More expensive and insurance coverage may vary..
What are common ultrasound findings associated with Edwards Syndrome?
-Growth restriction.
-Structural anomalies, such as rocker-bottom feet, clenched fists with overlapping fingers, and congenital heart defects (VSD).
Omphalocele, neural tube defects, or cystic hygroma.
What is the genetic cause of Jacobs Syndrome, and how does it arise?
Extra Y chromosome -> 47XYY karyotype.
Not inherited; arises de novo due to paternal nondisjunction during meiosis II.
This nondisjunction is more likely to occur in older fathers, advanced paternal age (>40 years) is a risk factor
What are the typical clinical features of Jacobs Syndrome?
Physical: Taller than average stature, normal sexual development, and typically no distinctive physical abnormalities.
Behavioral and neurodevelopmental concerns:
Increased risk of learning disabilities (especially language and reading).
Mild motor delays and coordination issues.
Impulsivity, attention deficits, and sometimes traits of autism spectrum disorder.
Medical: Slightly increased risk of asthma and seizures, normal testosterone levels, and fertility.
How is Jacobs Syndrome detected?
There are no U/S findings at any point to indicate Jacobs so through NIPS and confined with CSV/amnio.
NIPS: Sensitivity (Detection Rate): ~90–95%, Specificity: ~99%
Positive Predictive Value (PPV): Depends on maternal age and prevalence. Jacobs PPV is relatively lower due to prevalence (~1 in 1,000 male births).
