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

遗传咨询
ZHANG Xian-Ning, PhD
E-mail: [email protected]
Tel：13105819271; 88208367
Office: C303, Teaching Building
2015/09
Genetic Counseling
The American Board of Genetic Counseling
was established in the early 1990s, and now
various types of geneticists, including genetic
counselors遗传咨询师, 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
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
VI. Continuing clinical assessment,
especially if no diagnosis
Population Risk
• 2%-3% (3%-5%) for Birth Defects
and/or Intellectual disability
• 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
Chromosomal disorder:
Recurrence risk?
• Chromosomal syndromes usually have
a low recurrence risk. (The observed
frequency of a recurrence is taken as an
Empirical经验 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:
–
–
–
–
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:
–
–
–
–
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
AR
AR: Recurrence risk?
AD
AD: Recurrence risk?
XR
XR: Recurrence risk?
XR: Recurrence risk?
XD
XD: Recurrence risk?
Normal female (XX)
Affected
male
XA
(XAY)
Y
X
XA X
XY
Y-linked Disorders: Recurrence risk?
Mt. inheritance: Recurrence risk?
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!)
Cystic
fibrosis :
AR.
∴ ?’s risk of
being an
affected =1/22
×2/3 ×1/4 =
1/34≈0.75%
Spina bifida脊
柱裂:
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.
假设 1
II-2 is a carrier
Prior probability
Conditional
probability
Joint probability
Posterior
probability
1/2
(1/2)4=1/16
假设 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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