Prenatal Genetics

Owen Phillips, MD

Reproductive Genetics

Objectives:Predicting fetal health

as it pertains to genetic issues

1.Learn counseling issues concerning family history

2. Understand forms and indications for prenatal testing and screening

3% of all babies- major congenital anomaly.

Causes of birth defects:

1. Genetic factors– 14%

2. Environmental factors- 7%

3. Multifactorial (combination of 1 and 2)- 25%

4. Unknown etiology- 54%

Patient (Reproductive) History

• Previously affected offspring

• Stillbirths

• Spontaneous abortions

• Infertility and ART

• Teratogenic exposure

• Pedigree

Risk Factors for Offspring with a Chromosome Abnormality

• Maternal age (>35)

• Previous affected (1-2%)

• Maternal serum screening

• Ultrasound findings– Specific risk depends on abnormality

• Carrier of chromosome rearrangements– Most ascertained because of spontaneous

losses

Counseling

• Purposes, potential results and the implications of results

• Routine genetic screening is routinely offered, not routinely performed

• Tests should not be performed without the knowledge of the patient

Amniocentesis

• > or = 14 weeks gestation

• Loss rate 1/1000 above baseline risk

• Infection/injury to fetus- <1/1000

• Accuracy > 99.5 % detection rate chromosome abnormalities

Amniocentesis

First-trimester Prenatal Diagnosis

1. Alleviate stressful aspects of prenatal testing

2. Provides privacy concerning pregnancy management decisions

3. Safety of first- versus second-trimester termination

Testing must prove to be safe and accurate as traditional amniocentesis.

CVSTranscervical

CVSTransabdominal

Summary of CVS

• In experienced hands, loss rate from CVS comparable to Amnio

• TC and TA CVS risks comparable

• Infection rate (1/1000) similar amniocentesis

• As accurate as Amniocentesis

Screening for chromosome abnormalities

• Second trimester- a blood test– hCG, estriol, AFP– 60% Down syndrome

• First trimester- U/S and blood test– Certified sonosgrapher– PAPP-A, hCG

Autosomal Dominant Disorders

• Adult polycystic kidney disease

• Achondroplasia• Ehlers-Danlos

sydrome, type 1• Familial

hypercholesterolemia• Familial colonic

polyposis

• Huntington disease• Marfan syndrome• Myotonic dystrophy• Neurofibromatosis• Noonan syndrome

Autosomal Recessive Disorders

• Alpha-1-antitrypsin deficiency

• Congenital adrenal hyperplasia (21-hydroxylase deficiency)

• Cystic fibrosis• Homocystinuria• Meckel-Gruber syndrome• Thalassemia (alpha and

beta)

• Phenylketonuria

• Refsum disease

• Sickle cell anemia• Tay-Sachs disease• Wilson disease• Hurler syndrome

X-Linked Recessive Diseases

Duchenne muscular distrophyHemophilia BEhlers-Danlos syndrome, type V Hunter syndrome (Mucopolysaccharidosis II) Glucose-6-phosphate deficiency Fragile XHemophilia ALesch-Nyham syndrome

Family history of single gene defects

• Need information prior to pregnancy- specific disease

• Takes months + to define mutations

• Early prenatal diagnosis- may take weeks to make a diagnosis

Physician’s Concerns

• Family History of MR

• Ethnic background

• Ultrasound Findings

• Results of screening tests

• Teratogen exposure

Ethnic background

• Jewish

• Greek / Mediterranean

• African-American

• Asian

Ashkenazic Jewish Heritage

“Jewish panel” for carrier detection– Tay-Sachs– Canavan– CF– +/- non-classical Gaucher– Bloom syndrome– Nieman-Pick– Familial Dysautonomia

Other Ethnicities

• Mediterranean– Beta Thalassemia

• African American– Beta Thalassemia– Sickle Cell

• Asian-American– Beta Thalassemia– Alpha Thalassemia

The Future is Here

• All patients will be candidates for having information about their pregnancies

• Screening all low risk pregnancies

• Offered by various companies

• Impact? Candidates?

Microarray testing for 63 genetic disorders

using 1755 unique probes

Drawbacks

• Cost

• ‘Fishing’- parents may carry benign mutation

• Counseling to explain each disease to give a couple enough information

• Maybe in a certain setting with informed consent on the front end

Ultrasound to diagnose genetic disorders

• Specific findings associated with specific disease

Ultrasound is a genetic screening tool

• Fetal survey– 16-18 weeks

Drugs and Chemicals

Pregnant women take an average of 4 drugs during pregnancy

40% of these drugs are taken during the critical period associated with teratogenicity

Teratogenic agents

1) Drugs and chemicals

2) Infectious agents

3) Radiation

4) Other