Introduction to Risk Calculation in Genetic Counseling Book

Genetic Counseling and the Laws of Probability     3
Genetic Counseling and the Concept of Risk     3
The Laws of Probability     5
The Binomial Distribution     8
Bayes' Theorem     11
Case Scenario     14
Autosomal Dominant Inheritance     18
Reduced Penetrance     18
Disorders with Late Onset (Age-Dependent Penetrance)     27
Variable Expression     30
Parents Have Two Different Autosomal Dominant Disorders     31
Parents Have the Same Autosomal Dominant Disorder     34
Affected Siblings Born to Unaffected Parents     35
Anticipation     38
Autosomal Recessive Inheritance     42
Hardy-Weinberg Equilibrium     42
Risk to the Offspring of a Healthy Sibling     43
Risks to the Extended Family     46
Risks to the Offspring of an Affected Homozygote     49
Two Brothers Marry Two Sisters     50
Siblings with Different Autosomal Recessive Disorders     53
Allowing for Separate Mutations     54
Consanguinity     58
Direct Mutation Analysis and Multiple Alleles     64
Case Scenario     67
X-Linked RecessiveInheritance     70
The Prior Probability That a Female Is a Carrier of an X-Linked Recessive Disorder     71
The Probability That the Mother of an Isolated Case Is a Carrier     72
The Carrier Risks for Female Relatives of an Isolated Case     73
Different Mutation Rates in Males and Females     81
Biological Fitness Is Greater Than Zero     86
Case Scenario     90
The Use of Linked DNA Markers     93
Basic Principles of Genetic Linkage     93
Autosomal Dominant Inheritance     95
Autosomal Recessive Inheritance     98
X-Linked Recessive Inheritance     103
Using Information from Flanking Markers     105
Disorders with Late Onset     109
Parental Genotypes Not Known     111
Linkage Disequilibrium     114
Linkage Heterogeneity     116
Case Scenario     118
Germline Mosaicism     120
What is Germline Mosaicism?     120
A Simplified Model of Gametogenesis     121
Applying This Simple Model     124
Risk Estimates for Use in Counseling     125
Case Scenario 1     127
Case Scenario 2     129
Polygenic and Multifactorial Inheritance     131
Polygenic Inheritance and the Normal Distribution     132
The Liability/Threshold Model     134
General Principles in Counseling for Multifactorial Disorders     135
Computer Program for Risk Estimation     137
The Use of Susceptibility Loci     139
Cancer Genetics     144
Breast Cancer     145
Colorectal Cancer     153
Balanced Chromosome Rearrangements     158
Reciprocal Translocations     160
Robertsonian Translocations     170
Three-Way Translocations     175
Pericentric Inversions     177
Paracentric Inversions     181
Insertions     183
Rearrangements Involving an X Chromosome     186
Case Scenario     188
Other Mechanisms of Inheritance     192
X-Linked Dominant Inheritance     192
X-Linked Dominant Inheritance with Male Lethality     193
X-Linked Dominant Inheritance with Male Sparing     194
Metabolic Interference     195
Digenic Inheritance     196
Uniparental Disomy and Imprinting     197
Somatic Crossing-Over     201
Meiotic Drive      202
Mitochondrial Inheritance     203
References     207
Appendices
Ultrasound and Prenatal Diagnosis     219
Overlapping Normal Distributions     224
Length of Prometaphase Chromosome Segments     227
Index     239