Genetic Counseling and Prenatal Diagnosis Dr. Hassan Nasrat FRCS & FRCOG Professor Dept. Obstetrics & Gynecology King Abdulaziz University Hospital

Obstetricians are increasingly encountering couples who have worries about particular problem or disorder It is essential then to understand:  The various Methods used for prenatal screening and diagnosis and their limitation.  Adequate understanding of the basic principles of genetic inheritance, gene structure and analysis.

Genetic Counselling

Genetics consultation is evaluation of an individual or family Member Regarding a Genetic Disorder or Its Risk. Genetics Consultation

A genetics consultation involves the following:  A genetic condition : To diagnose or rule out  Calculating genetic risk ( i.e. probability of developing and/or transmitting it)  Discuss issues of medical management (consequences of this disorder and ways in which the disorder my be prevented or ameliorated)  Providing or arranging for psychosocial support

INDICATIONS FOR GENETIC COUNSELING  A known or suspected hereditary disease in the patient or a family member  Maternal age of 35 years or older during a pregnancy  Teratogen exposure during pregnancy  Ethnic background associated with an increased prevalence of a heritable disorder  Recurrent pregnancy loss  Identification of abnormalities during an antenatal sonogram  Abnormal results on first or second trimester screening test.  Family history of early onset cancer

Important Issues in Genetic Counseling:  The Genetic counseling make no directive suggestions.  There is no “right” or “wrong” decision but the decision should be the right one for the patient own situation.  Success or failure should not be judged on terms of a particular outcome.  The family should be given support for whatever decisions they may take. Ethical and Legal Aspects of genetic testing on patients and other family members.

In genetic counselling there is hardly yes or no answer. Often information are given in terms of probability or odds: Risks and Odds: What is the risk of a particular member in a family, born or unborn, having or developing the particular disorder? Likelihood of developing the disease

Odds Percentages 1 in

Empiric Risk: Is based on observed data rather than on theoretical predictions. E.g. most non-mendelian or chromosomal disorders. The is further affected by: - The accuracy of the diagnosis. - The population being studied Mendelian Risk: In case of single gene inherited disorders, whether a dominant, recessive or sex linked disorder. Other Factors: PENETRANCE (i.e. likelihood of developing disease given inheritance of disease- causing mutation) EXPRESSIVITY (i.e. phenotypic variations in the way the disease is expressed). Likelihood of developing the disease

The recommendations are: The woman improve her blood glucose level prior to conception (ideally HbA1c less than 8 percent) to reduce the risk of diabetic embryopathy. We offered the couple genetic testing to identify mutations that cause NF1 and XHED. The information could then be used for preimplantation or prenatal diagnosis ( although in neither case would knowledge of the mutation be likely to predict the severity of the condition in the fetus ).

Prenatal Diagnosis

Prenatal Screening and Prenatal Diagnosis  Developments of New Methods for Early screening.  Developments of Tests for Fetal tissue Sampling.  Developments in the Technology of Genetic Testing.

Prenatal Diagnosis Non-Invasive Invasive Techniques Amniocentesis Chorion Villus Sampling Fetal Blood Sampling Fetal Tissue Sampling Ultrasound Scanning Biochemical Markers Analysis of Fetal Cells In Maternal Blood Analysis Of Fetal Cells in Transcervical Samples Pre-Implantation Diagnosis

Rationale for prenatal screening and diagnosis Parental awareness Option of TOP –Karyotype: 32% –Structural: 68% Avoidance of inappropriate delivery/ resuscitation Optimal timing / mode / place of delivery In-utero therapy ?Reducing PMR, because of tops for fetal anomaly

 To Identify A Specific Disease Among Asymptomatic Individuals.  Non Invasive.  The Result Will Usually Changes ( Either or ) a Woman Risk of Having a Baby With the Disorder.  Targeted Screening: Is systematic testing of Selected Group considered to be at High Risk. Screening Tests

 For A Specific Diagnosis In Patients Who Have Actively Sought Health Care Or Following A Positive Screening Test.  Usually Invasive, Has A Measurable Degree Of Risk For The Fetus.  The Risk Of Doing The Test Should Be Balanced against The Risk Of Having The Disease. Diagnostic Tests

Maternal Age. Biochemical Tests: Maternal Serum AFP (e.g. For NTD and DS) Triple Test Weeks. Detailed U/S Weeks. Fetal Nuchal Translucency Screening for DS. Fetal Cells in Maternal Blood. Screening Tests

Amniocentesis. Chorion Villus Sampling. Fetal Blood & Tissue Sampling. Fetal Cells in Cervical Brush. Diagnostic Tests

Pre-Implantation Genetic Diagnosis PGD. Alternative Reproductive Options

Biochemical Screening tests §Alpha Fetoprotein Screening for NTD (AFP) §Biochemical Markers for DS.

Biochemical screening Free beta HCG AFP PAPP-A Oestriol Inhibin2 nd trimester

Factors Influence AFP §GA: the level of AFP increase by about 15% per week. §Maternal Weight: §Race: §IDD: §Multiple Pregnancy: §Family history of NTD:

§Women above 35 years has 1:250 risk of having DS baby §The risk of amniocentesis 1%. §Only 5% of pregnant population are > 35 years of age. §Not all of them accept amniocentesis Thus only 30 % of DS are identified if age alone is used as criteria for diagnosis Maternal Age as Screening for DS

Screening Tests for DS Biochemical –1 st trimester Quadruple blood test –2 nd trimester Double, triple test Ultrasound –1 st trimester The wk NT scan –2 nd trimester Routine anomaly scan Integrated Combined Sequential

Markers Values at 17 weeksActual Gestation MOM Risk at 17 wk. Apparent Risk of DS using combination of markers for a a woman at 37 years old Wald & Cukle 1992 Biochemical Screening in Prenatal Diagnosis

Ultrasound as a Screening for fetal anomalies

ULTRASOUND Direct Visualization of the Malformation. Facilitate Other Diagnostic Techniques. Accurate Fetal Measurement to Maximize performance of other Tests

§A ‘normal’ scans mean that no abnormalities were observed. §The ability to identify abnormalities depends on several factors: §Technical factors: The skill of the sonographer the time available to perform the scan and the quality of the equipment used. §Biological factors: maternal size, fetal position and age and amniotic fluid volume.

TV US during the 1 st trimester showing measurement of fetal NT. The cursors are placed on the inner aspect of the white line describing the NT. The widest part of the neck should be measured.

The NT scan NT

Amniocentesis

CHORIONIC VILLUS SAMPLING

Syncytiotrophoblast Cytotrophoblast Inner Mesoderm “ Require days in culture” “ Mitotically active, yield metaphase spread for direct exam.” Anatomy of Mature Placental Villi

Fetal Blood Sampling

Pre-Implantation Genetic Diagnosis PGD

Ethical Principle