E-mail: zhangxianning@zju.edu.cn Office: C303, Teaching Building 遗传咨询 ZHANG Xian-Ning, PhD E-mail: zhangxianning@zju.edu.cn 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? 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 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 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

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 XY

Y-linked Disorders: Recurrence risk?

Mt. inheritance: Recurrence risk?

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!)

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. 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.

∴ III-5’s risk of being a carrier=1/2 ×1/17=1/34≈3% 假设 1 II-2 is a carrier 假设 2 II-2 is NOT a carrier Prior probability 1/2 Conditional 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 ————=16/17 ∴ 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 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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