Prenatal Genetics Flashcards
What are 2 examples of abnormalities in chromosome number?
Triploidy (3n)
Aneuploidy
Triploidy
Definition
Prevalence
Prognosis
- Euploid complement of standard diploid (2n) chromosome number
- 3rd extra set of chromosomes (46 –> 69)
- 1-3% of pregnancies
- Lethal in virtually all cases
- Prognosis depends on parent of origin
What is Digynic Triploidy?
- Extra chromosome set of maternal origin
- Small placenta
- Fetus exhibits severe growth restriction
- Spontaneous abortion early in pregnancy
What is Diandric Triploidy?
What are women at risk for?
- Extra chromosome set of paternal origin
- Enlarged placenta
- Fetus is NOT growth restricted
- Partial Hydatidiform mole
- Women at risk for:
- Severe early onset preeclampsia
- Hyperthyroidism
- Multiple theca lutein cysts
- Gestational trophoblastic disease
What is Aneuploidy?
- Any other chromosome # that is not an exact multiple of haploid (n)
- Most common type of human chromosome disorder (5%)
What are some pathologic examples of aneuploidy? (5)
- Trisomy 21 (Down Syndrome)
- Trisomy 18 (Edwards Syndrome)
- Trisomy 13 (Patau Syndrome)
- Monsomy X (Turner Syndrome)
- XXY Syndrome (Klinefelter Syndrome)
Trisomy 21 (Down Syndrome)
Clinical Manifestation
- 1:800 live births
- Cognitive deficiencies
- Vision problems
- Hearing loss
- Thyroid dysfunction
- Increased risk for early onset dementia or cancer
- Congenital anomalies (heart malformations, GI abnormalities)
Trisomy 18 (Edwards Syndrome)
Clinical Manifestation
- 1:3,000 live births
- Severe psychomotor delays
- Growth restriction
- Microcephaly
- Micrognathia
- Distinctive hand/finger posturing
- Congenital anomalies (heart malformations, Omphalocele, oral clefting, clubfoot)
Trisomy 13 (Patau Syndrome)
Clinical Manifestation
- 1:10,000 live births
- Severe psychomotor delays
- Micropthalmia
- Polydactyly
- Congenital anomalies (oral clefting, holoprosencephaly, brain abnormalities, heart malformations, diaphragmatic hernia)
Monosomy X (Turner Syndrome)
Clinical Manifestation
- 1:2,500 live born females
- Growth retardation
- Infertility
- Hearing loss
- Possible cognitive disabilities
- Congenital anomalies (heart malformations, cystic hygromas, horseshoe kidney & other renal abnormalities)
XXY Syndrome (Klinefelter Syndrome)
Clinical Manifestation
Risk
- Tall/lean build
- Infertility
- Slightly delayed motor & language milestones
- Possible cognitive disabilities
-
Increased risk
- Extragonadal germ cell tumors
- Male breast cancer
- Autoimmune disorders
Risk for aneuploidy ________ with maternal age.
Increases
-
Singleton pregnancy (_>_35 YO)
- Risk of Down Syndrome = 1:385
- Risk of any aneuploidy = 1:204
-
Twin pregnancy (_>_33 YO)
- Risk of Down Syndrome = 1:347
- Risk of any aneuploidy = 1:176
Translocation
Definition
Balanced vs. Unbalanced
- Structural breakage & rearrangement of chromosome material
- 1:375 live births
- Spontaneous or transmitted from parent to offspring
-
Balanced
- Exchange of chromosome segments
- Not deleted (lost) or duplicated (gained)
- Carriers
- Normal phenotype
- 5-10% risk of passing on unbalanced
- Low risk (1%) vs. high risk (>20%)
-
Unbalanced
- Chromosome segments that are deleted or duplicated
Deletion
Definition
Phenotype
- Loss of segment of a chromosome (any length/size)
- 1:7,000 live births
- Chromosomal imbalance (partial monosomy)
- Phenotype results from haploinsufficiency
- Inability of a single copy of a genetic unit to perform the function of 2 copies
Duplication
Definition
- Gain of a segment of a chromosome (any length/size)
- Less common than deletions
- Chromosomal imbalance (partial trisomy)
What tests are done to screen for maternal serum and/or fetal ultrasound markers?
- 1st trimester screen
- Cell-free fetal DNA/Non-invasive Prenatal Screening (NIPS)
- Maternal Serum Quad Screen
What is the 1st trimester screen for pregnant patients?
What are the indications?
- Routine test
- Risk assessment
- Down Syndrome
- Trisomy 13
- Trisomy 18
- **Indicated for ALL pregnant patients regardless of fetal aneuploidy risk **
What is the Cell-free DNA/Non-invasive Prenatal Screening (NIPS)?
What are the indications?
- Non-routine test
- Risk assessment
- Down Syndrome
- Trisomy 13
- Trisomy 18
- Sex chromosome abnormalities
-
Indicated for high-risk pregnant patients
- Advanced maternal age
- Previous pregnancy or + FaHx of aneuploidy
- Abnormal fetal ultrasound
- Screening blood test suggestive of chr abnormality
What is the Maternal Serum Quad Screening test for pregnant patients?
- Routine test
- Risk assessment
- Down syndrome
- Trisomy 18
- Neural tube defects (spina bifida, anencephaly)
- Abdominal wall defects (Gastroschisis)
- **Indicated for all pregnant patients regardless of fetal aneuploidy risk **
What are 3 examples of Genetic Diagnostic Testing?
- Chorionic Villus Sampling
- Amniocentesis
- Cordocentesis/Percutaneous Umbilical Blood Sampling (PUBS)
Chorionic Villus Sampling
Definition
Indications
Procedure
- Prenatal diagnosis of fetal aneuploidy, other chromosome abnormalities & single gene disorders
- Does not screen for neural tube defects
- Indications
- Advanced maternal age
- FaHx
- Abnormal 1st trimester screen
- Available to all pregnant patients
- **Sample of placental chorionic villi obtained by transabdominal or Transcervical biopsy **
Amniocentesis
Definition
Indications
Procedure
- Prenatal diagnosis of fetal aneuploidy, other chromosome abnormalities, single gene disorders, abnormal biochemical levels
-
Amniotic fluid AFP analysis & AChE to detect:
- Open neural tube defects
- Abdominal wall defects
- Indications
- Advanced maternal age
- FaHx or abnormal screen
- Available to all pregnant patients
- Sample of amniotic fluid obtained via transabdominal biopsy
- Floating fetal cells used for culture, chromosomal & DNA analysis
**Cordocentesis/Percutaneous Umbilical Blood Sampling (PUBS) **
Indications
Procedure
-
Follow-up
- Amniocentesis fails or is ambiguous
- Biochemical tests of fetal plasma/blood cells or infection need to be confirmed
- Sample of fetal blood directly from umbilical vein
- Ultrasound guidance or infusion of blood products
Development vs. Dysmorphism
- Development – cellular pathways responding to environmental & genetic signals
- Dysmorphism – morphological, developmental abnormalities of 1 or more tissues or organ systems due to environmental or genetic factors
How can environmental factors alter fetal development?
What are the risk factors?
What are some examples?
- Environmental agents or maternal infections can be teratogenic
- Ability to alter fetal gene products & cellular communication
- Increased risk
- Birth defects, unusual facial characteristics, growth retardation, miscarriage, preterm birth, hearing loss, vision loss, cognitive deficiencies, behavior abnormalities
-
Maternal teratogen exposure
- Alcohol, smoking, illicit drugs, prescription medications, radiation
How does Alcohol act as a teratogen?
- Maternal consumption of 8-10 drinks/day
- Affects cellular pathways
- Central nervous system
- Craniofacial structures
How do illicit drugs (cocaine) act as teratogens?
- Fetal growth retardation
- Premature growth
- Neonatal complications
- Abnormal behavioral testing
- CV or respiratory problems
- Vasoconstrictive problems
- Skeletal abnormalities
- Genitourinary abnormalities
- **Cocaine excreted into breast milk **
How does Retinoic Acid (Isotretinoin) act as a teratogen?
- Accutane - oral medication for severe acne
- CNS abnormalities
- Craniofacial abnormalities
- Heart defects
- Cognitive deficiencies
- Retinoic acid is a natural component in breast milk (suppresion of bone growth, teeth stain)
How does Valproic Acid act as a teratogen?
- Oral anticonvulsant medication
- Neural tube defects
- Oral clefts
- Craniofacial abnormalities
- Heart defects
- Cognitive deficiencies
- Valproic acid can be excreted into breast milk
How do Selective Serotonin Reuptake Inhibitors (SSRIs) act as teratogens?
- Example: Zoloft
- Overall risk not above general population
- Cardiac malformations
- Neural tube defects
-
SSRIs in 3rd trimester: withdrawal symptoms
- Irritability
- Tremors
- Poor feeding & sleeping
- Arrhythmia
- Pulmonary depression
- Fetal distress
- **SSRIs are excreted into breast milk **
**Multifactorial Inheritance **
Definition
Risk Assessment
- Complex inheritance – trait/phenotype that results from an unclear combination of genetic & environmental factors
- Affected individuals may cluster in families
- Relatives likely to share predisposing alleles
- Risk assessment: population-based incidence of trait & degree of relationship w/i family of affected & non-affected individuals
**Multifactorial Inheritance **
Examples
- Pyloric stenosis
- Spina bifida
- Oral clefts
- Diabetes Mellitus
- Mental illness
What are Single Gene Mendelian Disorders?
-
Inherited in patterns of Mendelian inheritance
- Autosomal dominant
- Autosomal recessive
- X-linked
- Ancestry-based carrier screening offered to women of reproductive age
Single Gene Mendelian Disorders
- Euro/Caucasian (Northern)
- Euro/Caucasian (Southern)
- French Canadian
- African American
- Asian
- Latino
- Ashkenazi Jewish
Aside from common ancestry-related diseases, additonal disorders such as _________________ are becoming more prevalent in carrier screening discussion with patients.
**Fragile X Syndrome **
Fragile X Syndrome
Clinical Manifestation
Risk
Inheritance
- Mild to profound mental retardation, behavioral abnormalities, autistic tendencies, macrocephaly & other subtle facial characteristics
- Increased risk
- Premature ovarian failure among females
- Adult-onset cerebellar ataxia/intention disorders
- Abnormal repeats of DNA code w/i X chromosome
- X-linked pattern of inheritance
-
Carrier mothers asymptomatic
- Sons (50% affected)
- Daughters (50% asymptomatic carriers)
