Transcript GC is a communication process that deals with the human problems

Genetic Counseling
ZHANG Xian-Ning, PhD
E-mail: [email protected]
Tel：13105819271; 88208367
Office: A705, Research Building
2012/09
Genetic Counseling
The American Board of Genetic Counseling
was established in the early 1990s, and now
various types of geneticists, including genetic
counselors, medical geneticists, and basic
human geneticists, can be certified.
Genetic Counseling (ASHG, 1975)
“GC is a communication process that deals with the
human problems associated with the occurrence or risk of
occurrence of a genetic disorder in a family. This process
involves an attempt by one or more appropriately trained
persons to help the individual or family to (1) comprehend
the medical facts, including the diagnosis, probable course
of the disorder, and the available management; (2)
appreciate the way heredity contributes to the disorder
and the risk of recurrence in specified relatives; (3)
understand the alternatives for dealing with the risk of
recurrence; (4) choose a course of action that seems to
them appropriate in their view of their risk, their family
goals, and their ethical and religious standards, and act in
accordance with that decision; and (5) make the best
possible adjustment to the disorder in an affected family
member and/or to the risk of recurrence of that disorder."
Genetic Counseling (NSGC, 2006)
“GC is the process of helping people understand
and adapt to the medical, psychological, and
familial implications of genetic contributions of
disease. The process integrates the following: (1)
interpretation of family and medical histories to
assess the chance of disease occurrence or
recurrence; (2) education about inheritance, testing,
management, prevention, resources, and research;
and (3) counseling to promote informed choices
and adaptation to the risk of the condition."
The Medical Genetics Team
• Master’s level genetic counselor
• MD Geneticist
• Laboratory support:
– Molecular Genetics
– Biochemical Genetics
– Cytogenetics
• Ancillary Personnel:
– Nurse, Social Worker, Dietician
– Surgeons, Dentists
– Psychiatrists, Neurologists, Oncologists,
Pathologists
– Physical Therapist, Developmental Specialist
What Makes Genetics Evaluation
Different?
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Comprehensive approach to medical problem
Defining Etiology
Discuss implication of diagnosis
Discuss implication for family members
Giving bad news
Combining diagnostic evaluation and
counseling
Common indications for referral (I)
1. Previous child with multiple congenital
anomalies,mental retardation or an
isolated birth defect,such as neural tube
defect,cleft lip and palate.
2. Family history of a hereditary condition,
such as cystic fibrosis,fragile X
syndrome,or diabetes.
3. Prenatal diagnosis for advanced maternal
age or other indication.
Common indications for referral (II)
4. Consanguinity.
5. Teratogen exposure,such as to
occupational chemicals, medications,
alcohol.
6. Repeated pregnancy loss or infertility.
7. Newly diagnosed abnormality or genetic
condition.
Common indications for referral (III)
8. Before undertaking genetic testing and
after receiving results,particularly when
testing for susceptibility to late-onset
disorders,such as cancer or neurological
disease.
9. As follow-up for a positive newborn test,as
with PKU,or a heterozygote screening
test,such as Tay-Sachs.
GC Case Management
I. Collection of information
Family history (questionnaire)
Medical history
Tests or additional assessments
GC Case Management
II. Assessment
Physical examination
Lab and radiological testing
Validation or establishment of diagnosis—
if possible
GC Case Management
III. Counseling
Nature and consequence of disorder
GC Case Management
IV. Recurrence risk再发风险
Availability of further or future testing
Recurrence risk:The probability that a genetic
disorder present in one or more members of a
family will recur in another member of the same
or a subsequent generation.
GC Case Management
V. Decision making
Referral to other specialists, health
agencies, support groups
GC Case Management
VI. Continuing clinical assessment,
especially if no diagnosis
GC Case Management
VII. Psychosocial support
Population Risk
• 2%-3% (3%-5%) for Birth Defects
and/or Mental Retardation
• 33% of all pediatric admissions are
due to genetic causes
Factors increasing Risk - 1
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Maternal Age
Paternal Age
Ethnicity
Family history considerations
Factors increasing Risk - 2
• Exposures
• Abnormal first/second trimester
screening tests
• Abnormal ultrasound
Genetic Disorder
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Chromosomal disorder
Single-gene disorder
Mitochondrial genetic disorder
Multifactorial disorder
Somatic cell genetic disorder
Chromosomal disorder:
Recurrence risk?
• Chromosomal syndromes usually have
a low recurrence risk. (The observed
frequency of a recurrence is taken as an
Empirical Recurrence Risk)
• Even when a parent carries a balanced
chromosome rearrangement, the
recurrence risk among the offspring is
usually less than 15%.
Chromosomal disorder:
Recurrence risk?
• Rank the following, from lowest to highest, in
terms of the risk of producing a child with
Down syndrome:
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45-year-old woman with no previous family history
of Down syndrome
25-year-old woman who has had one previous
child with Down syndrome
25-year-old male carrier of a 21/14 Robertsonian
translocation
25-year-old female carrier of a 21/14 Robertsonian
translocation
Chromosomal disorder:
Recurrence risk?
• Rank the following, from lowest to highest, in
terms of the risk of producing a child with
Down syndrome:
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45-year-old woman with no previous family history
of Down syndrome → ~3%
25-year-old woman who has had one previous
child with Down syndrome → 1%
25-year-old male carrier of a 21/14 Robertsonian
translocation → 1%-2%
25-year-old female carrier of a 21/14 Robertsonian
translocation → 10%-15%
Gardner RJM,
Sutherland GR,
Shaffer LG.
Chromosome
Abnormalities and
Genetic Counseling.
4th ed. Oxford
University Press,
2011.
Single-gene disorder
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Mendelian
Autosomal dominant: Achondroplasia; Marfan
syndrome; Neurofibromatosis type 1
Autosomal recessive: Albinism; Cystic fibrosis; PKU
X-linked dominant: Hypophosphatemic rickets
X-linked recessive: DMD; Hemophilia A and B; G6PD
deficiency; Lesch-Nyhan syndrome
Y-linked: Haired ears
Nonmendelian
Triplet repeats: Fragile X syndrome; Myotonic
dystrophy; Spinocerebellar ataxia; Friedreich ataxia
Genomic imprinting: Prader-Willi syndrome; Angelman
syndrome
Mitochondrial: LHON; MERRF; MELAS
Mode of inheritance
AR
Some characteristic patterns in pedigree
·Affected offspring usually born to unaffected parents
· Chance of affected offspring is 25% for children of carriers
· If both parents are affected, all children will exhibit trait
· Affects either sex
· Increased incidence with parental consanguinity
AD
Affected individual has at least one affected parent
Children with one affected parent have 50% risk of being affected
Affects either sex
XR
· Affects almost exclusively males
· Not transmitted from father to son
· If female inherits, father must have trait
XD
All daughters of affected fathers exhibit the trait
All sons of an unaffected mother will not have trait
Y-linked
· Females never exhibit trait
· Son always has same phenotype as father
Mt inheritance
All children of an affected mother inherit the disorder
None of the children of an affected father inherit the disorder
AR
AR: Recurrence risk?
AD
AD: Recurrence risk?
XR
XR: Recurrence risk?
XR: Recurrence risk?
XD
XD: Recurrence risk?
Normal female (XX)
Affected
male
(XAY)
X
X
XA X
Y
XY
A
Y-linked Disorders
Mitochondrial inheritance
Trinucleotide CAG repeat sizes in
Huntington disease
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Normal ≤26
Mutable 27-35
Reduced penetrance 36-39
Fully penetrance ≥40
The effect of imprinting on
chromosome 15 deletions
Multifactorial disorder:
Recurrence risk?
• The sibling recurrence risks for multifactorial
conditions are usually 5% or less.
• The risk of recurrence in first-degree relatives of
affected individuals may be increased over the
background incidence of the disease in the
population.
• Recurrence risks are estimated empirically by
studying as many families with the disorder as
possible and observing how frequently the
disorder recurs. (Empirical recurrence risk!)
The Process of Genetic Counseling!
• 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 or
PGD
• Outline the various treatment or management
options for reducing the risk of disease.
Cystic
fibrosis :
AR.
∴ ?’s risk of
being an
affected =1/22
×2/3 ×1/4 =
1/34≈0.75%
Spina bifida :
Polygenic.
?’s risk of
being an
affected ≈4%
Down syndrome:
Chromosomal.
?’s risk of
being an
affected ≈1%
Bayesian analysis（Bayes定理）
• A mathematical method widely used in genetic
counseling to calculate recurrence risk.
• Posterior probability后概率=
Joint probability联合概率 / Σ Joint
probability联合概率之和
Joint probability=
Prior probability前概率×Conditional
probability条件概率
Hemophilia A :XR.The most common severe
inherited coagulation disorder caused by a
deficiency of factor VIII.
Hypothesis 1
II-2 is a carrier
Prior probability
Conditional
probability
Joint probability
Posterior
probability
1/2
(1/2)4=1/16
Hypothesis 2
II-2 is NOT a
carrier
1/2
1
1/2×1/16=1/32
1/2×1=1/2
1/32
1/2
————=1/17 ————=16/17
1/32+1/2
1/32+1/2
∴ III-5’s risk of being a carrier=1/2 ×1/17=1/34≈3%
The chance of III-6 is a carrier?
The chance of III-6 is a carrier?
Recurrence risk
Mary’s two brothers and her mother all had Duchenne
muscular dystrophy (DMD) and are now dead. Based
on only this information, what is the probability that
Mary is a heterozygous carrier for this disorder? What
is the probability that she will produce affected
offspring? Suppose Mary has a serum creatine kinase
(CK) test and is told that her level is above the 95th
percentile for homozygous normal individuals.
Approximately two thirds of DMD carriers have CK
levels above the 95th percentile. Given this information,
use Bayes theorem to calculate the probability that
Mary is a carrier and the probability that she will
produce affected offspring.
Mary is a
carrier
Mary is not a
carrier
Prior probability
1/2
1/2
Conditional probability that
her CK
is in the 95th percentile
Joint probability
2/3
0.05
1/3
0.025
Posterior probability
0.93
0.07
Since the probability that she would transmit the DMD
gene to her male offspring is 1/2, the probability of
producing an affected male increases from 0.25 to 0.47 (1/2
× 0.93).
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