Introduction to Risk Calculation in Genetic

Introduction to Risk Calculation in Genetic Counseling, third edition is designed for counselors and clinicians to provide them with an understanding of simple probability theory so that even the most reluctant mathematician will feel comfortable when providing risk assessment in a counseling situation. It is written in a friendly and relaxed style, avoiding the sort of complex and opaque formulae that grace the pages of bewildering textbooks on statistics. Each chapter addresses a specific pattern of inheritance with detailed explanations of basic principles and how these can be applied in practice. Numerous worked examples and case scenarios have been added to many of the chapters to emphasize clinical relevance.

Ian Young, MD, FRCP, is Honorary Professor and Consultant in Clinical Genetics at the Leicester Royal Infirmary, and formerly Assistant Editor of the Journal of Medical Genetics, who has written extensively about clinical aspects of Medical Genetics

1. Genetic Counseling and the Laws of Probability

3

(15)

1.1 Genetic Counseling and the Concept of Risk

3

(2)

1.2 The Laws of Probability

5

(3)

1.3 The Binomial Distribution

8

(3)

1.4 Bayes' Theorem

11

(3)

1.5 Case Scenario

14

(4)

2. Autosomal Dominant Inheritance

18

(24)

2.1 Reduced Penetrance

18

(9)

2.2 Disorders with Late Onset (Age-Dependent Penetrance)

27

(3)

2.3 Variable Expression

30

(1)

2.4 Parents Have Two Different Autosomal Dominant Disorders

31

(3)

2.5 Parents Have the Same Autosomal Dominant Disorder

34

(1)

2.6 Affected Siblings Born to Unaffected Parents

35

(3)

2.7 Anticipation

38

(4)

3. Autosomal Recessive Inheritance

42

(28)

3.1 Hardy-Weinberg Equilibrium

42

(1)

3.2 Risk to the Offspring of a Healthy Sibling

43

(3)

3.3 Risks to the Extended Family

46

(3)

3.4 Risks to the Offspring of an Affected Homozygote

49

(1)

3.5 Two Brothers Marry Two Sisters

50

(3)

3.6 Siblings with Different Autosomal Recessive Disorders

53

(1)

3.7 Allowing for Separate Mutations

54

(4)

3.8 Consanguinity

58

(6)

3.9 Direct Mutation Analysis and Multiple Alleles

64

(3)

3.10 Case Scenario

67

(3)

4. X-Linked Recessive Inheritance

70

(23)

4.1 The Prior Probability That a Female Is a Carrier of an X-Linked Recessive Disorder

71

(1)

4.2 The Probability That the Mother of an Isolated Case Is a Carrier

72

(1)

4.3 The Carrier Risks for Female Relatives of an Isolated Case

73

(8)

4.4 Different Mutation Rates in Males and Females

81

(5)

4.5 Biological Fitness Is Greater Than Zero

86

(4)

4.6 Case Scenario

90

(3)

5. The Use of Linked DNA Markers

93

(27)

5.1 Basic Principles of Genetic Linkage

93

(2)

5.2 Autosomal Dominant Inheritance

95

(3)

5.3 Autosomal Recessive Inheritance

98

(5)

5.4 X-Linked Recessive Inheritance

103

(2)

5.5 Using Information from Flanking Markers

105

(4)

5.6 Disorders with Late Onset

109

(2)

5.7 Parental Genotypes Not Known

111

(3)

5.8 Linkage Disequilibrium

114

(2)

5.9 Linkage Heterogeneity

116

(2)

5.10 Case Scenario

118

(2)

6. Germline Mosaicism

120

(11)

6.1 What is Germline Mosaicism?

120

(1)

6.2 A Simplified Model of Gametogenesis

121

(3)

6.3 Applying This Simple Model

124

(1)

6.4 Risk Estimates for Use in Counseling

125

(2)

6.5 Case Scenario 1

127

(2)

6.6 Case Scenario 2

129

(2)

7. Polygenic and Multifactorial Inheritance

131

(13)

7.1 Polygenic Inheritance and the Normal Distribution

132

(2)

7.2 The Liability/Threshold Model

134

(1)

7.3 General Principles in Counseling for Multifactorial Disorders

135

(2)

7.4 Computer Program for Risk Estimation

137

(2)

7.5 The Use of Susceptibility Loci

139

(5)

8. Cancer Genetics

144

(14)

8.1 Breast Cancer

145

(8)

8.2 Colorectal Cancer

153

(5)

9. Balanced Chromosome Rearrangements

158

(34)

9.1 Reciprocal Translocations

160

(10)

9.2 Robertsonian Translocations

170

(5)

9.3 Three-Way Translocations

175

(2)

9.4 Pericentric Inversions

177

(4)

9.5 Paracentric Inversions

181

(2)

9.6 Insertions

183

(3)

9.7 Rearrangements Involving an X Chromosome

186

(2)

9.8 Case Scenario

188

(4)

10. Other Mechanisms of Inheritance

192

(15)

10.1 X-Linked Dominant Inheritance

192

(1)

10.2 X-Linked Dominant Inheritance with Male Lethality

193

(1)

10.3 X-Linked Dominant Inheritance with Male Sparing

194

(1)

10.4 Metabolic Interference

195

(1)

10.5 Digenic Inheritance

196

(1)

10.6 Uniparental Disomy and Imprinting

197

(4)

10.7 Somatic Crossing-Over

201

(1)

10.8 Meiotic Drive

202

(1)

10.9 Mitochondrial Inheritance

203

(4)

References

207

(12)

Appendices

A1 Ultrasound and Prenatal Diagnosis

219

(5)

A2 Overlapping Normal Distributions

224

(3)

A3 Length of Prometaphase Chromosome Segments

227

(12)

Index

239

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Introduction to Risk Calculation in Genetic Counseling

Summary

Author Biography

Table of Contents

Supplemental Materials