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1 Definition of Genetic Counseling

  • A communication process which deals with the human problems associated with the occurrence, or the risk of occurrence, of a genetic disorder in a family

  • Involves an attempt by one or more appropriately trained persons to help the individual or family to

    • Comprehend the medical facts, including the diagnosis, probable course of the disorder, and available management

    • Appreciate the way heredity contributes to the disorder and the risk of recurrence in specified relatives

    • Understand the alternatives for dealing with the risk of recurrence

    • Choose the course of action which seems to them appropriate in view of their risk, their family goals, and their ethical and religious standards and to act in accordance with that decision

    • Make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder (ASHG 1975)

2 Role and Training of Genetic Counselors

  • Major role in the investigation and management of genetic disorders

  • Graduates of 2-year master’s level training programs in medical genetics and counseling

  • Board certification by the National Society of Genetic Counselors

  • Licensing required in some states

3 History of Genetic Counseling

  • In 1865, Gregor Mendel finds that individual traits are determined by discrete factors, later called genes, that are inherited from parents

  • In 1883, Francis Galton suggests that eugenics (Greek meaning wellborn) become the study of social policies that may improve or impair racial qualities of future generations either physically or mentally

  • In 1906, Bateson suggests the term “genetics” for the biological and medical study of heredity

  • By mid-1940s, heredity clinics were being established

  • By the 1950s, medicine began to focus on prevention and clinics established to advise people about inherited traits

  • In 1969, Sarah Lawrence College established first program in human genetics

  • In 1971, first ten “genetic associates” graduated from Sarah Lawrence

  • In 1975, term “genetic counseling” was coined by Sheldon Reed

4 Models of Genetic Counseling

4.1 Eugenic Model

  • Goal of eugenicists to improve the human species by better breeding

  • In 1904, Genetics Records Office opened at Cold Spring Harbor

  • In 1907, the state of Indiana passed the first sterilization law

  • When approved by a board of experts, the law mandated the sterilization of imbeciles, idiots, criminals, and others in state institutions

  • By 1926, 23 of the 48 states in the USA had laws mandating sterilization of the “mentally defective,” and over 6,000 people had been sterilized

  • Concept of eugenic sterilization found a receptive audience among the leadership of Nazi Germany

  • Sterilization of the unfit became a signature policy in the Nazi’s quest for racial purity and superiority

4.2 Medical/Preventive Model

  • Nazi excesses lead to a retreat from eugenics practices

  • Structure of DNA discovered in 1953

  • Few diagnostic tests available

  • Information about risk based on empirical observations offered to families so families could avoid recurrence of a disorder that had already occurred

  • Goal to prevent genetic disorders by offering families information and the option to avoid childbearing

  • Presumption that “rational” families would want to prevent recurrence

4.3 Decision-Making Model

  • Human diploid complement of 46 chromosomes reported in 1956

  • In late the 1950s and early 1960s, findings led to an understanding of the cytogenetics of Down, Klinefelter, and Turner syndromes

  • Trisomies 13 and 18 discovered

  • Became possible to identify those heterozygous for B-thalassemia and Tay-Sachs disease

  • Amniocentesis first used in 1956 for prenatal diagnosis initially for sex selection and later for karyotyping

  • Provided families with new options for assessing genetic risks and avoiding a genetic disorder

  • Legalization of abortion in 1972 meant that hard choices needed to be made regarding termination for genetic defects

  • Educating families about choices was labor intensive and time consuming

  • Because of the almost exclusive focus on reproduction, the ideal of nondirective counseling was embraced with emphasis on patient autonomy in decision making

  • Goals of counseling shifted from providing information to a process in which individuals were not only educated but helped to make decisions that were consistent with their own values and needs

4.4 Psychotherapeutic Model

  • Recognition that families cannot process or act on information they have been given unless they have dealt with the powerful emotions evoked by such information

  • New emphasis on exploring client’s experiences, emotional responses, goals, cultural expectations, religious beliefs, financial and social resources, family and interpersonal dynamics, and coping styles

5 Common Genetic Counseling Terms

  • Allele – One of the alternative versions of a gene that may occupy a given locus

  • Bayesian analysis – A mathematical method widely used in genetic counseling to calculate the risk of recurrence of a genetic disorder. This method combines information from a variety of sources including genetics, pedigree information, and test results to determine the probability that a specific individual may develop or transmit a specific disorder

  • Conditional probability – In Bayesian analysis, this is the chance of an observed outcome given the prior probability of the consultand’s genotype

  • Consanguinity – Relationship by descent from a common ancestor

  • Consultand – The individual requesting genetic counseling

  • Dominant – A trait is dominant if it is phenotypically expressed in heterozygotes

  • Empiric risk – The probability that a trait will occur or recur in a family based on past experience rather than on knowledge of the causative mechanism

  • Expressivity – The extent to which a genetic defect is manifested

  • Pedigree – A diagram of a family history indicating the family members, their relationship to the proband, and their status with regard to a particular genetic condition (affected vs. unaffected)

  • Joint probability – The product of the prior and conditional probabilities

  • Karyotype – The chromosomes of an individual. Also, a picture of the chromosomes of an individual arranged in a standard presentation

  • Penetrance – The probability that a mutant genotype will have any phenotypic expression

  • Phenotype – The observed biochemical, physiological, and morphological characteristics of an individual as determined by his or her genotype and the environment in which it is expressed

  • Proband – The family member through whom the family is ascertained. If affected, may be called the index case

  • Recessive – A trait of gene that expressed only in individuals who have inherited two copies of the gene

  • Recurrence risk – The probability that a genetic disorder present in one or more members of a family will recur in another member of the family of the same or subsequent generation

  • Teratogen – An environmental agent, medication, X-ray, or pathogen that produces or raises the incidence of congenital malformation

  • Variable expressivity – When the manifestation of a phenotype differs in people who have the same genotype

  • Variable penetrance – When a condition is expressed in less than 100% of individuals who carry the responsible allele

  • X-linked – Genes on the X chromosome or traits determined by such genes

  • Y-linked – Genes on the Y chromosome or traits determine by such genes

6 Common Genetic Counseling Problems

  • Single-gene disorders known or suspected

  • Multifactorial disorders known or suspected

  • Chromosomal disorders diagnosed in the consultand or family member

  • An abnormal trait or carrier state identified by genetic screening

  • Prenatal diagnosis for advanced maternal age or other indications

  • Consanguinity

  • Teratogen exposure

  • Repeated pregnancy loss or infertility

7 The Process of Clinical Genetics and Genetic Counseling

7.1 Prior to Clinic Visit

  • Reason for referral

  • Collection of family history information and construction of a pedigree

  • Collection and review of medical records and laboratory test results on consultand and other family members

7.2 Clinic Visit

  • Clinical examination

  • Diagnosis or ordering of further tests in order to make a diagnosis

  • Recurrence risk estimation

  • Genetic counseling

    • Nature and consequences of disorder

    • Recurrence risk

    • Means of modification of consequences

    • Means of prevention of recurrence

    • Management plan

7.3 Followup Care

  • Referral to appropriate clinical specialists

  • Referral to appropriate health agencies

  • Referral to appropriate support groups

  • Further clinical assessment if warranted

  • Continued contact and support by genetic counselor if needed

8 Determining Genetic Risks

8.1 Recurrence Risk Based on Known Genotype

8.1.1 Autosomal Recessive Disorders

  • For example, Tay-Sachs disease

  • Recurrence risk if both parents are known or obligate carriers is 25% for each future pregnancy [1/2 (chance that the mother passes on the mutation) × 1/2 (chance that the father passes on the mutation) = 1/4]

8.1.2 Autosomal Dominant Disorders

  • For example, achondroplasia

  • Recurrence risk if one parent is affected is 50% for each future pregnancy (chance that the parent passes on the mutation)

  • Factors to consider when counseling about an autosomal dominant condition in the absence of a positive family history

    • It could be the result of a new mutation in the proband

    • There may be decreased penetrance

    • There may variable expressivity

    • Germline mosaicism may be present in a parent

8.1.3 X-Linked Recessive Disorders

  • For example, Duchenne muscular dystrophy

  • Recurrence risk if mother is a known or obligate carrier is 25% for each future pregnancy [1/2 (chance that she passes on the mutation) × 1/2 (chance that she has a son) = 1/4]

8.1.4 X-Linked Dominant Disorders

  • For example, incontinentia pigmenti

  • These conditions are often lethal in males

  • One-third of the children of an affected female will be affected

  • All of the live-born males will be unaffected

  • Half of the females will be unaffected

  • One may also see an increase in the number of spontaneous abortions (affected male fetuses)

8.1.5 Mitochondrial Disorders

  • Cause by an mtDNA mutation, for example, Leber hereditary optic neuropathy

  • Recurrence risk if mother is a known mtDNA mutation carrier in a homoplasmic form is 100% for each future pregnancy

8.2 Recurrence Risks Using Empiric Data

  • Empiric recurrence risks are those in which the chance of having another affected individual in the family is based on observed data as opposed to mathematical calculations

  • Multifactorial or polygenic conditions

    • Empiric recurrence risks are available for numerous conditions, such as congenital heart defects, cleft lip and palate, diabetes, psychiatric disorders, and cardiovascular disease

    • The risk is greatest among first degree relatives and decreases with the distance of the relationship

    • The recurrence risk depends on the incidence of the condition

    • An estimate of the recurrence risk, when specific risk figures are not available, is the square root of the incidence of the condition (i.e., the recurrence risk is approximately one in 100 for a condition with an incidence of 1/10,000)

    • If there is an unequal sex incidence, the recurrence risk is greater for relatives of a proband of the sex in which the disorder is less common

    • The recurrence risk may increase if there are multiple affected family members and/or if the condition is more severe

8.2.1 Structural Chromosome Rearrangements

  • Empiric recurrence risks for those carrying common balanced chromosome rearrangements, such as a 14;21 Robertsonian translocation, are available

    • These risks may be dependent on sex of the transmitting parent (Table 24.1)

Table 24.1 The risk of having an abnormal liveborn may depend on the sex of the parent who carries the Robertsonian translocation
Full size table

8.2.2 Autosomal Dominant Conditions with Germline Mosaicism

  • There are some disorders in which the risk of germline mosaicism has been determined

  • For example, the chance that a parent of a child with osteogenesis imperfecta type 2 will have another affected child due to germline mosaicism is approximately 7%

8.3 Risk Assessment in Cases with Consanguinity

  • Consanguinity refers to relationships involving persons who share a common ancestor (i.e., are blood relatives)

  • The primary concern for children of these relationships is an increased risk of autosomal recessive disorders

  • The risk depends on the degree of relationship

    • The offspring of siblings have a one in eight chance of having an autosomal recessive disorder, while the risk for offspring of first cousins is 1 in 32

8.4 Bayesian Analysis in Risk Estimation

  • Bayesian analysis, which is based on Bayes theorem of probability, is a method for modifying one’s “prior” risk (i.e., risk based on Mendelian inheritance pattern or general population risk) using “conditional,” or phenotypic, information

8.4.1 Autosomal Dominant Disorders

  • Situations in which one may use Bayesian analysis include when the condition has reduced penetrance or variable expressivity or when the disorder has a late age of onset

  • For example, a man, whose mother had Huntington disease (HD), is currently asymptomatic at age 60. Given that 3/4 of individuals with a HD gene mutation will have symptoms by age 60, what is the chance that this man inherited the gene mutation from his mother?

  • Prior probability is the chance that this man inherited the mutation based on Mendelian risks (he had a one in two chance of inheriting it and a one in two chance of not inheriting it) (Table 24.2)

  • Conditional probability is the chance that this man is asymptomatic at age 60 if he did inherit the mutation [1/2 (chance he received the mutation) × 1/4 (chance he is asymptomatic with the mutation)] or that he is asymptomatic at age 60 if he did not (there is essentially a 100% chance he would be unaffected if he did not inherit the mutation) (Table 24.2)

  • The joint probabilities are the product of the prior and conditional probabilities (Table 24.2)

  • The posterior probabilities are the joint probability for the particular hypothesis divided by the sum of both joint probabilities (Table 24.2)

  • Therefore, this man has a one in nine (or approximately 11%) chance of having inherited the HD mutation from his mother given that he is asymptomatic at age 60 (compared to his prior risk of 50%) (Table 24.2)

Table 24.2 The posterior probability the man inherited the mutation given that he is asymptomatic at age 60
Full size table

8.4.2 Autosomal Recessive Disorders

  • One may use Bayesian analysis when the genotypes of one or both parents are not known

  • For example, a Caucasian couple of Northern European ancestry is referred for a maternal family history of cystic fibrosis

    • Cystic fibrosis is an autosomal recessive condition with a carrier frequency of approximately one in 25 in individuals with a Northern European ethnic background

    • The woman is a known mutation carrier

    • The man has also had CFTR gene testing

    • However, after being tested for the 87 most common mutations, no mutation was identified

    • The detection rate for this panel in individuals of his ethnicity is approximately 90% (one in ten will have a mutation that is not identified)

    • What is the chance that this couple will have a child with cystic fibrosis given the man’s gene test results?

  • Prior probability is the chance that this man has a mutation based on the carrier frequency in the population (he had a one in 25 chance of being a carrier and a 24 in 25 chance of not being one) (Table 24.3)

  • Conditional probability is the chance that this man tests negative if he does have a mutation [1/25 (chance he has mutation) × 1/10 (chance the test did not identify the mutation)] or that he tests negative if he is not a carrier (there is a 100% chance he would test negative if he does not have a mutation) (Table 24.3)

  • The joint probabilities are the product of the prior and conditional probabilities (Table 24.3)

  • The posterior probabilities are the joint probability for the particular hypothesis divided by the sum of both joint probabilities (Table 24.3)

  • Therefore, this man has a one in 251 (or a less than 1%) chance of being a carrier given that he tested negative (compared to his prior risk of one in 25 or 4%) (Table 24.3)

  • The chance that this couple will have a child with cystic fibrosis is one in 24,004 [1/6,001 (chance man is a carrier) × 1/4 (chance both parents pass on the mutation)]

Table 24.3 The probability that the father is a mutation carrier given that he had a negative gene test
Full size table

8.4.3 X-Linked Recessive Disorders

  • One may use Bayesian analysis when the possible carrier has had previously unaffected sons

  • For example, a 25-year-old woman is referred for prenatal genetic counseling because of a family history of hemophilia A (her sister and mother are obligate carriers of the factor VIII gene mutation)

    • Given that the client has already had two unaffected sons, what is the chance that the male fetus she is currently carrying will have hemophilia?

  • Prior probability is the chance that this woman is a carrier based on the Mendelian risks (she had a one in two chance of being a carrier and a one in two chance of not being one) (Table 24.4)

  • Conditional probability is the chance that this woman has two unaffected sons if she is a carrier [1/2 (chance that first son is unaffected) × 1/2 (chance that the second son is unaffected)] or that she has two unaffected sons if she is not a carrier (there is essentially a 100% chance she would have unaffected sons if she is not a carrier) (Table 24.4)

  • The joint probabilities are the product of the prior and conditional probabilities (Table 24.4)

  • The posterior probabilities are the joint probability for the particular hypothesis divided by the sum of both joint probabilities (Table 24.4)

  • Therefore, this woman has a one in five (or 20%) chance of being a carrier given that she has two unaffected sons (compared to her prior risk of one in two or 50%) (Table 24.4)

  • The chance that this woman’s unborn son is affected is one in ten [1/5 (chance that she is a carrier) × 1/2 (chance that she passes the mutation to him)]

Table 24.4 The probability the client is a carrier given she already had two unaffected sons
Full size table

8.4.4 Use of Molecular Genetics in Risk Assessment

  • Molecular genetic testing is currently available for hundreds of genetic conditions (www.ncbi.nlm.nih.gov/sites/GeneTests/)

  • Many techniques exist for the identification of a particular gene mutation (gene sequencing, PCR analysis, SSCP, other mutation scanning techniques)

  • Establishing a diagnosis, or identifying a gene carrier, by determining the gene mutation an individual carries allows a genetic counselor to provide a precise recurrence risk