Genetic Counselling andRisk Assessment

• Clinical genetics is concerned with the diagnosis and management of the medical, social, and psychological aspects of hereditary disease

• It is essential to make a correct diagnosis and to provide appropriate treatment, which must include helping the affected person and family members understand and come to terms with the nature and consequences of the disorder

• When a disorder is suspected of being heritable there is need to inform other family members of their risk and of the means available to them to modify these risks.

• Genetic counseling is not limited to the provision of information and calculation of the risk for disease; rather, it is a process of exploration and communication

• The ability to define and address the complex psychosocial issues associated with a genetic disorder in a family Geneticists and Genetic counselors can help with prevention and management, be a source of referral to specialists, and provide psychologically oriented counseling to help individuals adapt and adjust to the impact and implications of the disorder in the family

• Genetic counseling may be most effectively accomplished over time through periodic contact with the family as the medical or social issues become relevant to the lives of those involved

THE PROCESS OF GENETIC COUNSELING

Common Indications for Genetic Counseling• Genetic counsellors obtain a history that includes

family and ethnic information, advise patients of the genetic risks to them and other family members,

• Offer genetic testing or prenatal diagnosis when indicated, and outline the various treatment or management options for reducing the risk of disease

• Patients are not told what decisions to make with regard to the various testing and management options but are instead provided with information and support in coming to a decision that seems most appropriate for the patients

Managing the Risk of Recurrence in Families

• Many families seek genetic counseling to ascertain the risk for heritable disease in their children and to learn what options are available to reduce the risk of recurrence of the particular genetic disorder in question

• Although prenatal diagnosis is one approach that can often be offered to families, it is by no means a universal solution to the risk of genetic problems in offspring

Genetic laboratory tests (karyotyping, biochemical analysis, or DNA analysis) sometimes reassure couples with a family history of a genetic disorder that they themselves are OR not at increased risk of having a child with a specific genetic disease

Psychological Aspects

• Patients and families dealing with a risk for a genetic disorder or coping with the illness itself are subject to varying degrees of emotional and social stress

• Also true for non genetic illness

• These persons require much more support and may need referral for psychotherapy

Genetic counsellors:• Qualified professionals trained in genetics and

counseling participating in many aspects of the investigation and management of genetic problems.

• It helps patients and families deal with the many psychological and social issues that arise during genetic counseling, and continues in a supportive role and as a source of information after the clinical investigation and formal counseling have been completed

• They provide close liaison among the referring physicians, the diagnostic laboratories, and the families themselves

APPLICATION OF MOLECULAR GENETICS TO DETERMINATION OF RECURRENCE RISKS

• Many disease genes can now be detected directly in carriers and affected persons by means of DNA analysis.

• There are two chief approaches to risk estimation by DNA analysis. The first method is by direct detection of the mutation in a patient’s or other family member’s genomic DNA

• The second is the method of using flanking markers that are closely linked to the disease locus

Direct Detection of MutationsDuchenne Muscular Dystrophy• About 60% of patients with DMD have deletions within the

gene, and an additional 6% have duplicationsCystic Fibrosis• Most mutations in cystic fibrosis (CF) are single-base

mutations or deletions or duplications of a small number of nucleotides in the CFTR gene

• More than 1000 different mutations have been described in the CFTR gene.

• Some are rare, occurring in only a few families. Others are much more common, but their frequency can vary enormously in different ethnic groups

Use of Linked Markers in Molecular Diagnosis

• The linkage approach to mutation detection is indirect. One is not detecting the mutant allele itself but is using linked markers that flank the disease locus to track the inheritance of a gene known from the family tree to be harboring a disease-causing mutation.

Requirements:1. There is close linkage between the mutation and the marker, so that recombination is unlikely.2. The family is “informative”; that is, crucial family members are available for the study and are heterozygous for the markers.3. The linkage phase is known or can be reasonably inferred.4. No recombination has occurred between the markers being followed and the disease gene. If recombination does occur within the disease locus somewhere between the closely linked flanking markers

• Genetic counselors deal with many conditions that are not single-gene disorders. Instead, counselors may be called on to provide risk estimates for complex trait Disorders based on population surveys of birth defects in children born to first-cousin couples compared with non-consanguineous couples

• For example, neural tube defects (myelomeningocele and anencephaly) occur in approximately 0.3% of births in the U.S. white population.

• If, however, a couple has a child with a neural tube defect, the risk in the next pregnancy is 4% (13 times higher

• If these risk figures are calculated for different genders, the figures are even more striking: the sister of a girl with a neural tube defect has a 6% chance of also having a neural tube defect

DETERMINING RECURRENCE RISKS

• The estimation of recurrence risks is a central concern in genetic counseling.

• Ideally, it is based on knowledge of the genetic nature of the disorder in question and on the pedigree of the particular family being counseled.

• The family member whose risk of a genetic disorder is to be determined is usually a relative of a proband, such as a sib of an affected child or a living or future child of an affected adult

• In some families, especially for some autosomal dominant and X-linked traits, it may also be necessary to estimate the risk for more remote relatives

• When a disorder is known to have single-gene inheritance, the recurrence risk for specific family members can usually be determined from basic mendelian principles

• On the other hand, risk calculations may be less than straightforward if there is reduced penetrance or variability of expression, or if disease is frequently the result of new mutation, as in many X-linked and autosomal dominant disorders

• In contrast to single-gene disorders, the underlying mechanisms of inheritance for most chromosomal disorders and complex traits are unknown, and estimates of recurrence risk are based on previous experience

• This approach to risk assessment is valuable if there are good data on the frequency of recurrence of the disorder in families and if the phenotype is not heterogeneous

Risk Estimation When Genotypes Are Fully Known by Use of Mendel’s Laws• The simplest risk estimates apply to families in which

the relevant genotypes of all family members are known or can be inferred

• For example, if both members of a couple are known to be heterozygous carriers of an autosomal recessive condition, and one is interested in the chance of the couple’s having another affected child, the risk (probability) is one in four with each pregnancy that the child will inherit two mutant alleles and inherit the disease

Risk Estimation by Use of Conditional Probability When Alternative Genotypes Are Possible

• If the genotypes of the relevant individuals in the family are not definitively known; the risk of recurrence will be very different, depending on whether or not the consultand is a carrier of an abnormal allele of a disease gene.

• Bayesian analysis may seem like mere statistical maneuvering. However, the analysis allows genetic counselors to quantify what seemed to be naturally likely from inspection of the pedigree: e.g., the fact that the consultand had four unaffected brothers provides support for the hypothesis that her mother is not a carrier

In Family A, the mother II-1 is an obligate carrier for the X-linked bleeding disorder hemophilia A because her father was affected. Her risk of transmitting the mutant factor VIII (F8) allele responsible for hemophilia A is 1/2, and the fact that she has already had four unaffected sons does not reduce this risk. Thus, the risk that the consultand (III-5) is a carrier of a mutant F8 allele is ½ because she is the daughter of a known carrierIn Family B, however, the consultand’s mother (individual II-2) may or may not be a carrier, depending on whether she has inherited a mutant F8 allele from her mother, I-1. If III-5 were the only child of her mother, III-5’s risk of being a carrier would be 1/2 (her mother’s risk of being a carrier) × 1/2 (her risk of inheriting the mutant allele from her mother) = 1/4. Short of testing III-5 directly for the mutant allele, we cannot tell whether she is a carrier. In this case, however, the fact that III-5 has four unaffected brothers is relevant because every time II-2 had a son, the chance that the son would be unaffected is only 1/2 if II-2 were a carrier, whereas it is a near certainty (probability = 1) that the son would be unaffected if II-2 were, in fact, not a carrier at all. With each son, II-2 has, in effect, tested her carrier status by placing herself at a 50% risk of having an affected son. To have four unaffected sons might suggest that maybe her mother is not a carrier