Cytogenetics and Prenatal Flashcards
Triploidy
- 69, XXX or 69, XXY
- 1-2% incidence in conceptions
- 10% prevalence in miscarriages
- Typically results in miscarriage in the first trimester, but livebirths have been reported
Triploidy - Digyny
- Extra set of chromosomes are maternally derived
- Severe asymmetric fetal growth restriction with head sparing, small placenta
Triploidy - Diandry
- Extra set of chromosomes are paternally derived
- Enlarged, partially molar placenta
- Mild fetal growth restriction
- High NT and 10X higher maternal hCG
- Can cause maternal early pre-eclampsia and molar pregnancy/choriocarcinoma
Triploidy Syndrome
- Cystic placenta
- 3,4-syndactyly
- Unusual simian crease
Trisomy 13 (Patau Syndrome) Ultrasound Findings
- Holoprosencephaly
- Cystic hygroma
- Hydrops fetalis
- Omphalocele
Trisomy 18 (Edward Syndrome) Ultrasound Findings
- Clenched fists
- Choroid plexus cysts
- Rocker bottom feet
- Cystic hygroma
- Omphalocele
- Polyhydramnios
Trisomy 21 (Down Syndrome) Ultrasound Findings
- Echogenic bowel
- Increased NT in first trimester
- Increased NF in second trimester
- Cardiac defects
- Hypoplastic nasal bone
- EIF (weak)
Trisomy 21 Features
-Upslanted palpebral fissures
-Epicanthal folds
-Sandal gap
-BRUSHFIELD SPOTS IN IRIS
-Mild to moderate ID
-GI problems
-Hearing loss
-Hypotonia
-Short statue
-Congenital heart defects
-Hypothyroidism
-Increased risk for leukemia
-Decreased risk for solid tumors
~Occurs due to maternal or paternal MEIOSIS I non-disjunction~
Turner Syndrome
Most common chromosomal abnormality in miscarriage 45, X -Short stature -Webbed neck -Congenital heart defects - aortic stensosi -Amenorrhea -Cystic hygroma -Obesity -Widely spaced nipples -Learning difficulties/ADHD -Horseshoe kidney
Klinefelter Syndrome
47, XXY
- Tall stature
- Hypotonia
- Feminization at puberty: gynecomastia, broad hips, absent or reduced facial hair
- Reduced fertility
- Hypogonadism
- Increased risk for breast cancer
- Increased risk for thromboembolism
- Normal intelligence, may have reading or speech difficulties
Monosomy 1p36 (1p36 deletion syndrome)
- Developmental delay
- Mild to severe ID
- Limited or absent speech
- Aggression and self-injurious behavior
- Autistic behaviors
- Dysphagia
- Brain MRI abnormalities: Cerebral atrophy, ventricular asymmetry and/or enlargement, hydrocephalus
- Hyperreflexia
- Microcephaly
- Visual problems: strabismus, cataracts, hypermetropia, nystagmus
- Dysmorphic features: frontal bossing, small pointed chin, flat nose, deep-set eyes, thickened helices, slanting palpebral fissures, midface hypoplasia, orofacial clefting
- Hypotonia
- Hypothyroidism
- Heart defects: Infantile DCM, PDA, ToF
- Increased risk for neoplasm: neuroblastoma, prostate, lung, melanoma, hepatoma, cervical, breast, colorectal, ovarian, NHL
- hearing loss
- scoliosis/kyphosis
Trisomy 16
Most common TRISOMY
Always results in miscarriage/early termination
First Trimester Screening
Maternal serum levels of PAPP-A and hCG + ultrasound
ADJUSTS RISK for trisomy 18 and trisomy 21
- Trisomy 21 shows elevated hCG and decreased PAPP-A
- Trisomy 18 shows decreased hCG and decreased PAPP-A
- Results can be affected by maternal age, weight, race, and gestational diabetes
Quad Screen/Multiple Marker Screen
Maternal serum levels of hCG, inhibin A, uE3, AFP
ADJUSTS RISK for trisomy 18, trisomy 21, and neural tube defects (NTD)
- Trisomy 18 will show decreased hCG, decreased inhibin A, decreased uE3, decreased AFP
- Trisomy 21 will show increased hCG, increased inhibin A, decreased uE3, decreased AFP
- NTD increased risk when MoM (multiple of the median) for AFP is >2.0
- Results can be affected by maternal age (not AFP), weight, race, and gestational diabetes
NIPT
- Can detect some trisomies (typically 13, 18, 21, may detect others)
- Can detect some microdeletions and microduplications
- Can detect sex chromosome aneuploidy (to an extent)
- May detect triploidy (SNP-based method only (Natera))
Ultrasound
- First trimester ultrasound will measure nuchal translucency and crown-rump length
- Second trimester ultrasound (18-20 weeks) is considered the detailed or diagnostic ultrasound
- Will assess any structural abnormalities
NTD Ultrasound Findings
- Spina bifida – Lemon sign (Chiari II malformation), banana sign (cerebellum)
- Anencephaly
- Gastroschisis
Double Bubble Sign
Duodenal atresia
Amniotic Band Syndrome
Missing limbs or digits
Congenital absence of the cavus septum pellucidum (CSP)
Septo-optic dysplasia
Echogenic bowel
- Down syndrome
- Cystic fibrosis
- CMV infection
- Congenital narrowing of the bowel/bowel obstruction
Chorionic Villus Sampling (CVS)
- Diagnostic test
- Available between 11-13 weeks gestational age
- Samples placental tissue either transcervically or transabdominally
- Confined placental mosaicism may be present in 1-2% of cases
- Risk for miscarriage anywhere between 1/250 – 1/1000 depending on institution
Amniocentesis
- Diagnostic test
- Available at or after 16 weeks gestational age
- Samples amniotic fluid (baby pee ft. skin cells)
- Transabdominal
- Risk for miscarriage anywhere between 1/250 – 1/1000 depending on institution
Imprinting
- Selective silencing of paternal or maternal genes
- Genes are silenced (imprinted) through methylation during gametogenesis
- Paternally imprinted genes are silenced while the maternally derived copy is expressed
- Maternally imprinted genes are silenced while the paternally derived copy is expressed
Inversions
Pericentric – includes the centromere
-Can result in unbalanced offspring
Paracentric – does not include the centromere
- Usually results in acentric fragments/dicentric chromosomes
- Greater amounts of miscarriage
Karyoptype
- Shows an entire set of chromosomes with delineated bands
- Useful for visualizing large deletions, duplications, translocations, and inversions
- Resolution is too poor to detect microdeletions and duplications
Fluorescence in situ hybridization (FISH)
- Utilizes sequence complementary to the region of interest
- Fluorescent hybridization signals euploidy or aneuploidy of the region
- Can detect deletions >0.5-1Mb long and duplications >1 Mb long
- Resolution is too poor for smaller deletions/duplications
- Limited in that you must know what region to look for
- Useful for parental studies when CMA detects a large enough deletion or duplication in a child
- Useful for whole chromosome aneuploidy analysis (fast turnaround for trisomy 21, usually still confirmed with karyotype or CMA)
Chromosomal Microarray (CMA)
Oligo-array– detects microdeletions and duplications, cannot detect balanced rearrangements such as inversions and translocations
SNP-array – detects loss of heterozygosity/regions of heterozygosity, uniparental disomy, and triploidy
-Detected by quantitative change rather than CGH
MOST clinicians will utilize a combo oligo/SNP chip to have complete coverage
Limited by interpretation of CNVs – not all are pathogenic, some VUS
Indications for CMA
- Multiple congenital anomalies not specific to a well-delineated syndrome
- Idiopathic/non-syndromic developmental delay/intellectual disability
- Autism spectrum disorder
- Prenatal patients with one or more major structural anomalies on ultrasound
- May be useful for products of conception
