02/05/20231

Genetic Counseling & Prenatal Diagnosis

Dr. Dilip ChoudharyModerator: Dr. D. Singh

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Genetic Counseling

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Learning Objectives-O 1. What is genetic counseling?O 2. Why it is needed?O 3. What are the clinical situations

(indications) where it is important?O 4. Types of genetic counselingO 5. What are the steps of genetic

counseling?

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Introduction: O Genetic counseling is communicative

process which deals with human problems associated with occurrence and or recurrence of a genetic disorder in a family.

O An individual who seek genetic counselling is known as a consultand.

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This involves an attempt by counsellor to help the consultand to: Understand the medical facts including diagnosis,

probable course of disorder and available management.

Understand the mode of inheritance of the disorder and the risk of developing and/or transmitting it.

Understand the alternatives for dealing with the risk of recurrence.

Choose the course of action which is appropriate for them.

Make the best possible adjustment to the disorder in an affected family member and or to the risk of recurrence of the disorder.

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Purpose of genetic counseling Provide concrete, accurate information about inherited

disorders. Reassure people who are concerned that their child may

inherit a particular disorder that the disorder will not occur.

Allow people who are affected by inherited disease to make informed choice about future reproduction.

Educate people about inherited disorder and the process of inheritance.

Offer support by skilled health care professionals to people who are affected by genetic disorders.

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Indications1. Advanced parental age:- Maternal age ≥35 yrs Paternal age ≥50 yrs2. Previous child with or family H/O:- Congenital anomaly Dysmorphism Intellectual disability Isolated birth defect Metabolic disorder Chromosomal abnormality3.Adult onset genetic disorder (presymptomatic testing):- Cancer4.Consanguinity

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5.Teratogen exposure 6.Repeated pregnancy loss or infertility7.Pregnancy screening abnormality Maternal serum α-feto protein Maternal triple or quad test Fetal ultrasonography Fetal karyotype8.Heterozygote screening based on ethnic risk Sickle cell anemia Tay- sachs, Canavan, Gaucher disease Thalassemia9.Follow up to abnormal neonatal genetic testing

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Types of Genetic Counseling Two types of genetic counseling:(A) Prospective genetic counseling:• This allows for the true prevention of disease.• This requires to identify heterozygous individuals

for any particular defect by screening.• Explaining to them the risk of their having

affected children if they marry another heterozygote for the same gene.

• If heterozygous marriage can be prevented or reduced, the prospects of giving birth to affected children will diminish.

• Ex: Sickle cell anaemia Thalassemia

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(B) Retrospective genetic counseling:• Most genetic counseling at present is

retrospective, (the hereditary disorder has already occurred within the family).

• Ex. Mental retardation Psychiatric illness Inborn errors of metabolism• The methods which could be suggested under

retrospective genetic counseling are: Contraception Pregnancy termination. Sterilization

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Areas of genetic counseling:(A)Prenatal Genetic Counseling: Several different reasons a person or couple may seek

prenatal genetic counseling. If a woman is of age 35 or

older and pregnant, then there is an increased chance that

her fetus may have a change in the number of chromosomes

present.

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(B) Pediatric Genetic Counseling:Families or pediatricians seek genetic counseling when a

child has features of an inherited condition. Any child who

is born with more than one defect, mental retardation or

dysmorphic features has an increased chance of having a

genetic syndrome. A common type of mental retardation in

males for which genetic testing is available is fragile X-

syndrome.

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Steps of genetic counseling

History & Physical

examination

• Include present, past history, detailed family history, obstetric history including still births and abortions if any and exposure to teratogen.

• Careful examination of affected( photographs, measurement) and of apparently unaffected individuals in the family.

Pedigree

• Construct a 3 generation pedigree diagram with their age, sex and state of health.

Risk assessment

• One of the most important aspect, often called “recurrence risk”. Requires to take into account- Mode of inheritance Analysis of pedigree or family tree Results of various tests

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Diagnosis

• Most crucial step, confirm the diagnosis by available diagnostic tests.

Communication

• Transmitting the information, with ample time for discussion and questions.

Management

• Discuss available options for treatment of disease and prevention of known complications or prevention of genetic disorder( medical termination of pregnancy).

Support groups

• Group of patient or parents of children with same disorder (patient support group)

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Prenatal diagnosis

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O Introduction: procedures which are used to detect genetic disorders during early stages of pregnancy.

O Indications ;1. To identify fetal disease when abortion is

being considered.2. Direct fetal treatment

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Methods of prenatal diagnosis(a) Imaging- Ultrasound Fetoscopy MRI (b) Fluid analysis- Amniocentesis Cordocentesis (c) Fetal tissue analysis- Chorionic villus sampling (d) Maternal serum tests- α-feto protein Triple test Quad test (e) Maternal cervix- Fetal fibronectin Fluid Bacterial culture

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Non invasive methods

Imaging- USG, MRI

Maternal serum analysis

Invasive methods

Fluid analysis-Amniocentesis, Cordocentesis,

Fetal tissue analysis-

Chorionic villus sampling

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ImagingUltrasound–

O Real time USG can detect • fetal growth abnormalities- by biometric measurement of biparietal diameter, femoral length, or head or abdominal circumference.• Fetal anomalies eg. Hydrocephalus, NTDs, duodenal

atresia, diaphragmatic hernia, renal agenesis, limb anomalies, omphalocele, gastroschisis, hydrops.

• Also help in performing BPP, cordocentesis and other invasive procedures

O Doppler USG- for velocimetry and detection of increased vascular resistence due to fetal hypoxia.

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Fluid AnalysisChorionic villous samplingO Transvaginal or transabdominal chorionic villous biopsy, whichprovides fetal cells.The placenta contains tissue that is genetically identical to fetus.O Timing: In first trimester, shouldn’t be performed before 10wk, commonly performed between 11 and 13 wks.O Indications: for karyotype, enzyme assay, molecular

DNA genetic analysis.

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O Method of CVS: two ways to perform a CVS, transabdominally (TA) and transcervically (TC), depends on the location of the villi in the uterus.

Transabdominal approach-When the villi are anterior, under all aseptic precautions ultrasound guided needle is passed through abdominal Wall and the uterus to reachthe villi. A syringe attached to the needle is used to suction out a small amount of villi.

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Transcervical approach- When the villi are in the lower part of the uterus and posterior TC approach is used. A thin flexible plastic catheter is carefully guided through the cervix under ultrasound guidance to the villi. A syringe attached to the catheter is used to suction out a small amount of villi as the catheter is withdrawn.O The CVS procedure collects larger samples

and provides faster results than amniocentesis.

O Different from amniocentesis in that it does not allow for testing for neural tube defects.

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O Associated risk/ Complications: 1.miscarriage/ fetal loss (1% - 2%). 2. Oromandibular limb hypoplasia. 3.Isolated limb reduction defect- • Increased risk is associated with decreased

gestational age at the time of CVS, highest susceptibility when CVS if performed before 9 wks.

• Mechanism: thromboembolization or fetal hypoperfusion through hypovolemia or vasoconstriction (based on assumption that caused by some form of vascular disruption). The limbs and mandible are susceptible to such disruption before 10 weeks’ gestation.

• Overall risk for transverse limb deficiency from CVS is 0.03%–0.10%

4.Rh- isoimmunization.

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AmnicentesisO USG guided percutaneous withdrawal of amniotic fluid for diagnostic purpose.O Timing- between 14- 16wks.O Indications: • Karyotype (advanced maternal age)• Fetal maturity (L:S ratio, phosphatidylcholine or phosphatidylglycerol)• Biochemical enzyme/amino acid/hormone analysis.• Molecular genetic DNA diagnosis.• α- fetoprotein(for NTDs) and 17-ketosteroid (for adrenogenital syndrome) determination

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O Method of amniocentesis:Performed transabdominally (TA). During the procedure, a needle is passed through the abdomen and into the amniotic sac under continuous ultrasound guidance. The needle stilette is removed once the needle is in the correct position. A small sample of amniotic fluid (10–20ml) is then removed using a syringe attached to the needle.

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Complications of amniocentesis:1.Miscarriage (risk about 1%). Before 14 weeks of gestation (early amniocentesis) has a higher fetal loss rate.2.Preterm labor (stimulation of uterine contraction) or PROM.3.Injury to fetus4.Placental puncture and bleeding with secondary damage to fetus.5.Infection6. Maternal sensitization to fetal blood (Rh-isoimmunization) :- Anti D immunoglobulin to be given to Rh –ve mother.

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CVS Amniocentesis

What does it involve?

Small sample of placenta under ultrasound guidance

small sample of amniotic fluid under ultrasound guidance

When is the procedure usually performed?

Between 10 and 14 weeks of pregnancy

After 15 weeks of pregnancy

What is the risk of miscarriage?

About 1 to 2 in 100 women (1-2%)

About 1 in a 100 women (1%)

What technique is used?

transabdominally (TA) and transcervically (TC)

transabdominally (TA)

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CordocentesisO Cordocentesis, or PUBS (Percutaneous Umbilical Blood Sampling), is the sampling ofblood from the umbilical cord.O Objective: (a) prenatal diagnosis and (b) fetal

therapy.O Timing: can be performed as early as 16 wks

of gestation but commonly performed between 18-22 wks of gestation for prenatal diagnosis.

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O Indication of cordocentesis:(a) Prenatal diagnosis:• Detection of anemia, hemoglobinopathies,

thrombocytopenia, acidosis, hypoxia, polycythemia

• Immunoglobuline M antibody response to infection

• Rapid karyotype and molecular DNA genetic diagnosis.

(b) Fetal therapy:• Transfusion or administration of drugs.

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O Method of cordocentesis:Under ultrasound guidance needle is inserted in the umbilical vein within the umbilical cord at its placental end or fetal end. Upon entering the umbilical cord, the stylet is removed and fetal blood is withdrawn into a syringe attached to the hub of the needle.The needle is withdrawn, then the puncture site is monitored for bleeding, and the fetal heart rate is assessed. After this procedure, the fetal heart rate and uterine contraction are monitored for 1-2 hours.

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O Complications:• Pregnancy loss, overall fetal loss risk of 1- 2%.• Transient fetal bradycardia, manifestations of a

vasovagal response caused by local vasospasm, more with umbilical artery puncture.

• Bleeding from the puncture site, cord hematoma.• Fetomaternal hemorrhage • Premature labor• Infection• Rh iso- immunization

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Maternal serum test(A) α- feto protein:Incresed Decreased• Twins Trisomies• NTDs Aneuploidy• Intestinal atresia• Fetal demise(B) Triple test: can detect 70% of Down syndrome• Unconjugated estriol ↓ed• α- feto protein ↓ed• Β-HCG ↑ed(C) Quad test: can detect 80% of Down syndrome.• Unconjugated estriol ↓ed• α- feto protein ↓ed• β-HCG ↑ed• Inhibin ↑ed[Note: if only 1st trimester quad screen is used, α-feto protein is recommended as a 2nd trimester follow up]

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Down syndrome screening:(A) 1st trimester:• Fetal nuchal translucency (NT) thickness

alone ≤70%• NT with β-HCG & PAPP-A 87% (PAPP-A = Pregnancy Associated Palsma Protein- A)

(B) 2nd trimester:• Triple test 70%• Quad test 80%

(C) Integrated screen:1st trimester screen + 2nd trimester screen detect 95%

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Maternal cervixO Fetal fibronectin: indicates risk of preterm

birth.O Bacterial culture: identifies risk of fetal

infection (group B streptococcus, Neisseria gonorrhoeae).

O Fluid: determination of PROM.

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THANK YOU