Genetic Counseling

ZHANG Xian-Ning, PhD

E-mail: zhangxianning@zju.edu.cn

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."

• 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

The Medical Genetics Team

What Makes Genetics Evaluation Different?

• 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

• Maternal Age

• Paternal Age

• Ethnicity

• Family history considerations

Factors increasing Risk - 2

• Exposures

• Abnormal first/second trimester screening tests

• Abnormal ultrasound

Genetic Disorder

• 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:

– 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 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 Some characteristic patterns in pedigree

AR ·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

XA

XA X

Y XY

Y-linked Disorders

Mitochondrial inheritance

Trinucleotide CAG repeat sizes in Huntington disease

• 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

Hypothesis 2

II-2 is NOT a carrier

Prior probability 1/2 1/2Conditional probability

(1/2)4=1/16 1

Joint probability 1/2×1/16=1/32 1/2×1=1/2

Posterior probability

1/32

————=1/17

1/32+1/2

1/2

————=16/17

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 riskMary’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

2/3 0.05

Joint probability 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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