Prenatal Genetics

Question 1

What are 2 examples of abnormalities in chromosome number?

Answer 1

Triploidy (3n)

Aneuploidy

Question 2

Triploidy

Definition

Prevalence

Prognosis

Answer 2

• 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

Question 3

What is Digynic Triploidy?

Answer 3

• Extra chromosome set of maternal origin
• Small placenta
• Fetus exhibits severe growth restriction
• Spontaneous abortion early in pregnancy

Question 4

What is Diandric Triploidy?

What are women at risk for?

Answer 4

• 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

Question 5

What is Aneuploidy?

Answer 5

• Any other chromosome # that is not an exact multiple of haploid (n)
• Most common type of human chromosome disorder (5%)

Question 6

What are some pathologic examples of aneuploidy? (5)

Answer 6

• Trisomy 21 (Down Syndrome)
• Trisomy 18 (Edwards Syndrome)
• Trisomy 13 (Patau Syndrome)
• Monsomy X (Turner Syndrome)
• XXY Syndrome (Klinefelter Syndrome)

Question 7

Trisomy 21 (Down Syndrome)

Clinical Manifestation

Answer 7

• 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)

Question 8

Trisomy 18 (Edwards Syndrome)

Clinical Manifestation

Answer 8

• 1:3,000 live births
• Severe psychomotor delays
• Growth restriction
• Microcephaly
• Micrognathia
• Distinctive hand/finger posturing
• Congenital anomalies (heart malformations, Omphalocele, oral clefting, clubfoot)

Question 9

Trisomy 13 (Patau Syndrome)

Clinical Manifestation

Answer 9

• 1:10,000 live births
• Severe psychomotor delays
• Micropthalmia
• Polydactyly
• Congenital anomalies (oral clefting, holoprosencephaly, brain abnormalities, heart malformations, diaphragmatic hernia)

Question 10

Monosomy X (Turner Syndrome)

Clinical Manifestation

Answer 10

• 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)

Question 11

XXY Syndrome (Klinefelter Syndrome)

Clinical Manifestation

Risk

Answer 11

• Tall/lean build
• Infertility
• Slightly delayed motor & language milestones
• Possible cognitive disabilities
• Increased risk
  
  • Extragonadal germ cell tumors
  • Male breast cancer
  • Autoimmune disorders

Question 12

Risk for aneuploidy ________ with maternal age.

Answer 12

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

Question 13

Translocation

Definition

Balanced vs. Unbalanced

Answer 13

• 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

Question 14

Deletion

Definition

Phenotype

Answer 14

• 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

Question 15

Duplication

Definition

Answer 15

• Gain of a segment of a chromosome (any length/size)
• Less common than deletions
• Chromosomal imbalance (partial trisomy)

Question 16

What tests are done to screen for maternal serum and/or fetal ultrasound markers?

Answer 16

• 1st trimester screen
• Cell-free fetal DNA/Non-invasive Prenatal Screening (NIPS)
• Maternal Serum Quad Screen

Question 17

What is the 1st trimester screen for pregnant patients?

What are the indications?

Answer 17

• Routine test
• Risk assessment
  
  • Down Syndrome
  • Trisomy 13
  • Trisomy 18
• **Indicated for ALL pregnant patients regardless of fetal aneuploidy risk **

Question 18

What is the Cell-free DNA/Non-invasive Prenatal Screening (NIPS)?

What are the indications?

Answer 18

• 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

Question 19

What is the Maternal Serum Quad Screening test for pregnant patients?

Answer 19

• 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 **

Question 20

What are 3 examples of Genetic Diagnostic Testing?

Answer 20

• Chorionic Villus Sampling
• Amniocentesis
• Cordocentesis/Percutaneous Umbilical Blood Sampling (PUBS)

Question 21

Chorionic Villus Sampling

Definition

Indications

Procedure

Answer 21

• 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 **

Question 22

Amniocentesis

Definition

Indications

Procedure

Answer 22

• 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

Question 23

**Cordocentesis/Percutaneous Umbilical Blood Sampling (PUBS) **

Indications

Procedure

Answer 23

• 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

Question 24

Development vs. Dysmorphism

Answer 24

• 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

Question 25

How can **environmental factors** alter fetal development? What are the risk factors? What are some examples?

Answer 25

* **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

Question 26

How does **Alcohol** act as a teratogen?

Answer 26

* Maternal consumption of _8-10 drinks/day_ * Affects cellular pathways * Central nervous system * Craniofacial structures

Question 27

How do **illicit drugs** (cocaine) act as teratogens?

Answer 27

* 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 **

Question 28

How does **Retinoic Acid** (Isotretinoin) act as a teratogen?

Answer 28

* **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)**

Question 29

How does **Valproic Acid** act as a teratogen?

Answer 29

* **Oral anticonvulsant medication** * Neural tube defects * Oral clefts * Craniofacial abnormalities * Heart defects * Cognitive deficiencies * **Valproic acid can be excreted into breast milk**

Question 30

How do Selective Serotonin Reuptake Inhibitors (**SSRIs**) act as teratogens?

Answer 30

* 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 **

Question 31

**Multifactorial Inheritance ** Definition Risk Assessment

Answer 31

* **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

Question 32

**Multifactorial Inheritance ** Examples

Answer 32

* Pyloric stenosis * Spina bifida * Oral clefts * Diabetes Mellitus * Mental illness

Question 33

What are **Single Gene Mendelian Disorders**?

Answer 33

* **Inherited in patterns of Mendelian inheritance** * Autosomal dominant * Autosomal recessive * X-linked * Ancestry-based carrier screening offered to women of reproductive age

Question 34

**Single Gene Mendelian Disorders** * Euro/Caucasian (Northern) * Euro/Caucasian (Southern) * French Canadian * African American * Asian * Latino * Ashkenazi Jewish

Answer 34

Question 35

Aside from common ancestry-related diseases, additonal disorders such as _________________ are becoming more prevalent in **carrier screening discussion** with patients.

Answer 35

**Fragile X Syndrome **

Question 36

**Fragile X Syndrome** Clinical Manifestation Risk Inheritance

Answer 36

* 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)