Genomics in the Clinic: A Practical Guide to Genetic Testing, Evaluation, and Counseling

Genomics in the Clinic: A Practical Guide to Genetic Testing, Evaluation, and Counseling illustrates the current scope of the practice of genetics for healthcare professionals, so they can understand principles applicable to genetic testing and consultation. Written by an authoritative well-balanced team, including experienced clinical geneticists, genetic counselors, and medical subspecialists, this book adopts an accessible, easy-to-follow format. Sections are dedicated to basic genetic principles; clinical genetic and genomic testing; prenatal, clinical and cancer genetic diagnosis and counseling; and ethical and social implications in genomic medicine. Over 100 illustrative cases examine a range of prenatal, pediatric and adult genetic conditions and testing, putting these concepts and approaches into practice. Genomics in the Clinic: A Practical Guide to Genetic Testing, Evaluation, and Counseling is important for primary care providers, as patient care evolves in the current genomic-influenced world of precision medicine.

• Clearly explains central concepts of genetic testing and genomic medicine for non-genetic physicians, healthcare providers, and trainees
• Offers clear steps for clinical integration of genetic concepts, genomic technology, and interpretation of genetic test results approachable and relevant to clinical practice
• Descriptive, applied case studies illustrate recommended genetic evaluation, counseling and management for a range of conditions throughout the lifetime

• Language: English
• Publisher: Academic Press
• Release date: Nov 4, 2023
• ISBN: 9780128164792

Book preview

Genomics in the Clinic

A Practical Guide to Genetic Testing, Evaluation, and Counseling

Edited by

Antonie D. Kline, MD

Director of Clinical Genetics, Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, United States

Ethylin Wang Jabs, MD

Chair of the Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States

Adjunct Professor of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Adjunct Professor of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, United States

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

Foreword

Acknowledgments

Chapter 1. Introduction

Chapter 2. Basic Principles of Genetics and Genomics

2.1. Chromosome Structure and Function

2.2. Chromosome Variation

2.3. Molecular Structure and Function

2.4. Molecular Variation

2.5. Mitochondrial Structure and Function

2.6. Epigenome

2.7. Modes of Inheritance

2.8. Phenotypic Variation

Chapter 3. Genetic Counseling and Referrals

3.1. Preparation for Genetics Appointment

3.2. Family History and Genetic Background

3.3. Genetic Counseling

3.4. Genetic Risks for Family Members

3.5. Psychosocial Issues and Support Organizations

Chapter 4. Prenatal Genetics and Referrals

4.1. Carrier Screening

4.2. High-risk Pregnancy

4.3. Fetal Imaging

4.4. Prenatal Evaluation

4.5. Other Reproductive Options

Chapter 5. Clinical Genetics and Referrals

5.1. Congenital Anomalies and Dysmorphic Features

5.2. Developmental Disabilities and Behavioral Abnormalities

5.3. Growth Disorders

5.4. Metabolic Disorders

5.5. Adult Onset Conditions

5.6. Pharmacogenomic Testing

5.7. Genetics of Mental Illness

Chapter 6. Genetic and Genomic Testing

6.1. Cytogenetics and Cytogenetic Testing

6.2. Genotyping

6.3. Genome Testing

6.4. Other Specific Tests

6.5. Source of Sample (Blood, Saliva, Tissue)

6.6. Ordering Genetic and Genomic Tests

Chapter 7. Genetic and Genomic Results and Management

7.1. Interpretation of Results

7.2. Recommendations for Reporting Secondary Findings

7.3. Limitations of Genetic Testing

7.4. Management and Services Available with Genetic Diagnosis

Chapter 8. Cancer Genetics Referrals and Management

8.1. Hereditary Cancer Risk Assessment

8.2. Referral for Cancer Genetic Testing

8.3. Management Recommendations for Mutation-Positive Individuals

8.4. Follow-up after Cancer Genetic Testing

Chapter 9. Direct-to-Consumer Testing

9.1. Direct-to-Consumer Testing and Limitations

9.2. Ethical Considerations

9.3. Medical and Scientific Considerations

9.4. Risk and Benefits

9.5. Conclusions

Chapter 10. Ethical and Psychosocial Issues

10.1. The Informed Consent Process

10.2. Cost and Insurance Concerns

10.3. Secondary and Incidental Findings

10.4. Genetic Information Nondiscrimination Act

10.5. Reinterpretation of Findings and Patient Recontact

Chapter 11. Case Scenarios

Section 11.1. Prenatal Cases

Case 11.1.1. Prenatal Cases: Positive Carrier Screening in Pregnancy

The Case

The Issues

The Referral

The Diagnosis

Case 11.1.2. Prenatal Cases: Maternal Diabetes Exposure

The Case

The Issues

The Referral

The Diagnosis

Case 11.1.3. Prenatal Cases: Advanced Maternal Age

The Case

The Issues

The Referral

The Diagnosis

Case 11.1.4. Prenatal Cases: Noninvasive Prenatal Screening Positive for Sex Chromosome Abnormality

The Case

The Issues

The Referral

The Diagnosis

Case 11.1.5. Prenatal Cases: Fetal Anomalies

The Case

The Issues

The Referral

The Diagnosis

Case 11.1.6. Prenatal Cases: Clubfeet and Decreased Fetal Movement

The Case

The Issues

The Referral

The Diagnosis

Case 11.1.7. Prenatal Cases: Recurrent Pregnancy Loss

The Case

The Issues

The Referral

The Diagnosis

Case 11.1.8. Prenatal Cases: Preimplantation Genetic Testing for a Single Gene Disorder

The Case

The Issues

The Referral

The Diagnosis

Section 11.2. Newborn Screening Cases

Case 11.2.1. Newborn Screening Cases: False Positive Newborn Screening

The Case

The Issues

The Referral

The Diagnosis

Case 11.2.2. Newborn Screening Cases: Abnormal Newborn Metabolic Screening

The Case

The Issues

The Referral

The Diagnosis

Case 11.2.3. Newborn Screening Cases: Abnormal Newborn Hearing Screening

The Case

The Issues

The Referral

The Diagnosis

Case 11.2.4. Newborn Screening Cases: Abnormal Newborn Neuromuscular Screening

The Case

The Issues

The Referral

The Diagnosis

Section 11.3. Craniofacial Cases

Case 11.3.1. Craniofacial Cases: Congenital Microcephaly

The Case

The Issues

The Referral

The Diagnosis

Case 11.3.2. Craniofacial Cases: Misshapen Head

The Case

The Issues

The Referral

The Diagnosis

Case 11.3.3. Craniofacial Cases: Congenital Nystagmus

The Case

The Issues

The Referral

The Diagnosis

Case 11.3.4. Craniofacial Cases: Loss of Central Vision

The Case

The Issues

The Referral

The Diagnosis

Case 11.3.5. Craniofacial Cases: Bilateral Retinal Detachment

The Case

The Issues

The Referral

The Diagnosis

Case 11.3.6. Craniofacial Cases: Acquired Night Blindness

The Case

The Issues

The Referral

The Diagnosis

Case 11.3.7. Craniofacial Cases: Congenital Hearing Loss

The Case

The Issues

The Referral

The Diagnosis

Case 11.3.8. Craniofacial Cases: Hearing Loss and Renal Agenesis

The Case

The Issues

The Referral

The Diagnosis

Case 11.3.9. Craniofacial Cases: Hearing Loss and Night Blindness in a Teenager

The Case

The Issues

The Referral

The Diagnosis

Case 11.3.10. Craniofacial Cases: Cleft Palate

The Case

The Issues

The Referral

The Diagnosis

Section 11.4. Cardiovascular and Pulmonary Cases

Case 11.4.1. Cardiovascular and Pulmonary Cases: Recurrent Pneumonias

The Case

The Issues

The Referral

The Diagnosis

Case 11.4.2. Cardiovascular and Pulmonary Cases: Dyspnea with History of Neonatal Jaundice

The Case

The Issues

The Referral

The Diagnosis

Case 11.4.3. Cardiovascular and Pulmonary Cases: Pulmonic Stenosis and Short Stature

The Case

The Issues

The Referral

The Diagnosis

Case 11.4.4. Cardiovascular and Pulmonary Cases: Severe Palpitations

The Case

The Issues

The Referral

The Diagnosis

Case 11.4.5. Cardiovascular and Pulmonary Cases: Exercise-Induced Syncope

The Case

The Issues

The Referral

The Diagnosis

Case 11.4.6. Cardiovascular and Pulmonary Cases: Hyperlipidemia

The Case

The Issues

The Referral

The Diagnosis

Case 11.4.7. Cardiovascular and Pulmonary Cases: Myocardial Infarction in a Healthy Adult

The Case

The Issues

The Referral

The Diagnosis

Case 11.4.8. Cardiovascular and Pulmonary Cases: Cardiomyopathy and Peripheral Neuropathy

The Case

The Issues

The Referral

The Diagnosis

Section 11.5. Gastrointestinal Cases

Case 11.5.1. Gastrointestinal Cases: Bowel Obstruction in an Infant

The Case

The Issues

The Referral

The Diagnosis

Case 11.5.2. Gastrointestinal Cases: Elevated Liver Transaminases in an Infant

The Case

The Issues

The Referral

The Diagnosis

Case 11.5.3. Gastrointestinal Cases: Failure to Thrive

The Case

The Issues

The Referral

The Diagnosis

Case 11.5.4. Gastrointestinal Cases: Obesity, Hypotonia, and Peripheral Vision Loss

The Case

The Issues

The Referral

The Diagnosis

Case 11.5.5. Gastrointestinal Cases: Acute Abdominal Pain

The Case

The Issues

The Referral

The Diagnosis

Case 11.5.6. Gastrointestinal Cases: Abdominal Pain and Arthralgias

The Case

The Issues

The Referral

The Diagnosis

Section 11.6. Metabolic Cases

Case 11.6.1. Metabolic Cases: Sweet Smell in an Infant

The Case

The Issues

The Referral

The Diagnosis

Case 11.6.2. Metabolic Cases: Apparent Life-Threatening Event

The Case

The Issues

The Referral

The Diagnosis

Case 11.6.3. Metabolic Cases: Hypoglycemia in a Child

The Case

The Issues

The Referral

The Diagnosis

Case 11.6.4. Metabolic Cases: Recurrent Vomiting and Language Delay

The Case

The Issues

The Referral

The Diagnosis

Case 11.6.5. Metabolic Cases: Lactic Acidosis

The Case

The Issues

The Referral

The Diagnosis

Case 11.6.6. Metabolic Cases: Hunger and Protein Intake in a Metabolic Condition

The Case

The Issues

The Referral

The Diagnosis

Section 11.7. Endocrinologic and Growth Cases

Case 11.7.1. Endocrinologic and Growth Cases: Overgrowth

The Case

The Issues

The Referral

The Diagnosis

Case 11.7.2. Endocrinologic and Growth Cases: Macrocephaly and Tall Stature in a Toddler

The Case

The Issues

The Referral

The Diagnosis

Case 11.7.3. Endocrinologic and Growth Cases: Diabetes

The Case

The Issues

The Referral

The Diagnosis

Case 11.7.4. Endocrinologic and Growth Cases: Short Stature

The Case

The Issues

The Referral

The Diagnosis

Case 11.7.5. Endocrine and Growth Cases: Small Stature and Delayed Puberty

The Case

The Issues

The Referral

The Diagnosis

Case 11.7.6. Endocrine and Growth Cases: Pubertal Delay, Hearing Loss, and Lack of Smell

The Case

The Issues

The Referral

The Diagnosis

Section 11.8. Genitourinary Cases

Case 11.8.1. Genitourinary Cases: Ambiguous Genitalia

The Case

The Issues

The Referral

The Diagnosis

Case 11.8.2. Genitourinary Cases: Familial Renal Disease

The Case

The Issues

The Referral

The Diagnosis

Case 11.8.3. Genitourinary Cases: Renal Cysts

The Case

The Issues

The Referral

The Diagnosis

Section 11.9. Hematologic and Immunologic Cases

Case 11.9.1. Hematologic and Immunologic Cases: Bleeding Disorder

The Case

The Issues

The Referral

The Diagnosis

Case 11.9.2. Hematologic and Immunologic Cases: Recurrent Infections in Childhood

The Case

The Issues

The Referral

The Diagnosis

Case 11.9.3. Hematologic and Immunologic Cases: Chronic Thrombocytopenia in a Child

The Case

The Issues

The Referral

The Diagnosis

Case 11.9.4. Hematologic and Immunologic Cases: Thrombocytopenia in an Adult

The Case

The Issues

The Referral

The Diagnosis

Case 11.9.5. Hematologic and Immunologic Cases: Bone Marrow Failure

The Case

The Issues

The Referral

The Diagnosis

Section 11.10. Skeletal and Connective Tissue Cases

Case 11.10.1. Skeletal and Connective Tissue Cases: Asymmetric Leg Size in an Infant

The Case

The Issues

The Referral

The Diagnosis

Case 11.10.2. Skeletal and Connective Tissue Cases: Disproportionate Short Stature

The Case

The Issues

The Referral

The Diagnosis

Case 11.10.3. Skeletal and Connective Tissue Cases: Multiple Fractures

The Case

The Issues

The Referral

The Diagnosis

Case 11.10.4. Musculoskeletal Cases: Tall and Lean with Nonspecific Hip Pain

The Case

The Issues

The Referral

The Diagnosis

Case 11.10.5. Musculoskeletal Cases: Chronic Musculoskeletal Pain and Fatigue

The Case

The Issues

The Referral

The Diagnosis

Section 11.11. Dermatologic Cases

Case 11.11.1. Dermatologic Cases: Infant with Nystagmus and Fair Skin

The Case

The Issues

The Referral

The Diagnosis

Case 11.11.2. Dermatologic Cases: Multiple Café au Lait Spots

The Case

The Issues

The Referral

The Diagnosis

Case 11.11.3. Dermatologic Cases: Abnormal Teeth in a Toddler

The Case

The Issues

The Referral

The Diagnosis

Section 11.12. Neurodevelopmental Cases

Case 11.12.1. Neurodevelopmental Cases: Developmental Stagnation and Regression

The Case

The Issues

The Referral

The Diagnosis

Case 11.12.2. Neurodevelopmental Cases: Delayed Speech, Polydactyly, and Short Stature

The Case

The Issues

The Referral

The Diagnosis

Case 11.12.3. Neurodevelopmental Cases: Delayed Development in Early Childhood

The Case

The Issues

The Referral

The Diagnosis

Case 11.12.4. Neurodevelopmental Cases: Autism Spectrum Disorder

The Case

The Issues

The Referral

The Diagnosis

Case 11.12.5. Neurodevelopmental Cases: Cognitive Issues and Tall Stature

The Case

The Issues

The Referral

The Diagnosis

Section 11.13. Neurologic and Muscular Cases

Case 11.13.1. Neurologic and Muscular Cases: Congenital Hypotonia and Feeding Difficulties

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.2. Neurologic and Muscular Cases: Dysmorphic Features and Hypotonia

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.3. Neurologic and Muscular Cases: Seizures in an Infant

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.4. Neurologic and Muscular Disease: Clubfeet and Lack of Facial Expression

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.5. Neurologic and Muscular Cases: Abnormal Gait in a Toddler

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.6. Neurologic and Muscular Cases: Abnormal Movements and Posturing

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.7. Neurologic and Muscular Cases: Dystonia Family History

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.8. Neurologic and Muscular Cases: Slowness and Loss of Facial Expression in a Young Adult

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.9. Neurologic and Muscular Cases: Progressive Gait Impairment and Genitourinary Dysfunction

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.10. Neurologic and Muscular Cases: Progressive Ataxia

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.11. Neurologic and Muscular Cases: Intention Tremor and Difficulty with Balance

The Case

The Issues

The Referral

The Diagnosis

Case 11.13.12. Neurologic and Muscular Cases: Chorea

The Case

The Issues

The Referral

The Diagnosis

Section 11.14. Psychiatric Cases

Case 11.14.1. Psychiatric Cases: Early-Onset Dementia

The Case

The Issues

The Referral

The Diagnosis

Cases 11.14.2. Psychiatric Cases: Psychosis and Learning Disabilities

The Case

The Issues

The Referral

The Diagnosis

Case 11.14.3. Psychiatric Cases: Bipolar Disorder and Stevens–Johnson Syndrome

The Case

The Issues

The Referral

The Diagnosis

Section 11.15. Pharmacogenomic Cases

Case 11.15.1. Pharmacogenomic Cases: Warfarin for Atrial Fibrillation

The Case

The Issues

The Referral

The Diagnosis

Case 11.15.2. Pharmacogenomic Cases: Clopidogrel for Coronary Artery Disease

The Case

The Issues

The Referral

The Diagnosis

Case 11.15.3. Pharmacogenomic Cases: Thiopurine for Acute Lymphoblastic Leukemia

The Case

The Issues

The Referral

The Diagnosis

Section 11.16. Cancer Cases

Case 11.16.1. Cancer Cases: Breast Cancer Gene Mutation Found Incidentally

The Case

The Issues

The Referral

The Diagnosis

Case 11.16.2. Cancer Cases: Ovarian Cancer Family History

The Case

The Issues

The Referral

The Diagnosis

Case 11.16.3. Cancer Cases: Family History of Lynch Syndrome

The Case

The Issues

The Referral

The Diagnosis

Case 11.16.4. Cancer Cases: Prostate Cancer

The Case

The Issues

The Referral

The Diagnosis

Case 11.16.5. Cancer Cases: Pancreatic Cancer

The Case

The Issues

The Referral

The Diagnosis

Case 11.16.6. Cancer Cases: Adrenocortical Carcinoma and Leukemia

The Case

The Issues

The Referral

The Diagnosis

Case 11.16.7. Cancer Cases: Macrocytic Anemia and Idiopathic Pulmonary Fibrosis

The Case

The Issues

The Referral

The Diagnosis

Section 11.17. Direct-to-Consumer Cases

Case 11.17.1. Direct-to-Consumer Cases: Breast Cancer Family History

The Case

The Issues

The Referral

The Diagnosis

Case 11.17.2. Direct to Consumer Cases: Predisposition of a Multifactorial Condition by Direct-to-Consumer Testing

The Case

The Issues

The Referral

The Diagnosis

Case 11.17.3. Direct-to-Consumer Cases: Identification of Birth Family History by Direct-to-Consumer Testing

The Case

The Issues

The Referral

The Diagnosis

Case 11.17.4. Direct-to-Consumer Cases: Metabolic and Neurologic Disease Risk by Direct-to-Consumer Testing

The Case

The Issues

The Referral

The Diagnosis

Case 11.17.5. Direct-to-Consumer Cases: Risk for Late-Onset Alzheimer Disease by Direct-to-Consumer Testing

The Case

The Issues

The Referral

The Diagnosis

Case 11.17.6. Direct-to-Consumer Cases: Wellness Report By Direct-to-Consumer Testing

The Case

The Issues

The Referral

The Diagnosis

Section 11.18. Ethical Issues Cases

Case 11.18.1. Ethical Issues Cases: Predictive Testing in an Adolescent with Positive Family History

The Case

The Issues

The Referral

The Diagnosis

Case 11.18.2. Ethical Issues Cases: Preconception Sex Selection

The Case

The Issues

The Referral

The Diagnosis

Section 12. Communicating Genetics and Genomics

Chapter 12. Communicating Genetics and Genomics

12.1. Overview of Genetic Discussion with Families

12.2. Counseling about Genetic Concepts

12.3. Counseling about Genetic Tests

12.4. Counseling about Results

12.5. Concluding Remarks

12.6. Visual Aids to Explain Genetic Concepts to Families

Index

Copyright

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Notices

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Dedication

Together because of our love for the discipline of medical genetics, we dedicate this book to our patients and their families for the lessons they have taught us. We thank all our colleagues who have enhanced our clinical and research experiences.

Individually, we dedicate this book to:

Laird G. Jackson, M.D., who inspired me to enter the field of genetics and who was my mentor for many years; Tilde S. Kline and Irwin K. Kline, who were my role models as parents and in medicine; Julia, Eli and Conrad Clemens for their support always; and Douglas K. Clemens, who always provides encouragement and promotes resilience.

-Antonie D. Kline

Barbara Migeon, M.D., my mentor who helped me realize my goals, and my family of Shih Yi Wang, Chun Lien Wang, Robert T. Wang, Douglas A. Jabs, and Alexandra W. Jabs, who have always provided encouragement and support.

-Ethylin Wang Jabs

Contributors

Daniah Albokhari, MBBS,     Assistant Professor, Department of Pediatrics, Taibah University College of Medicine, Medina, Saudi Arabia

Houriya Ayoubieh, MD,     Assistant Professor, Department of Medical Education, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, United States

Manisha Balwani, MD, MS,     Professor and Chief, Division of Medical Genetics and Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Jessica C. Barry, MS, CGC,     Section of Genetic Counseling, Clinical Genetics Center, 22q and You Center, The Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, United States; LVPG Maternal Fetal Medicine, Lehigh Valley Health Network, Allentown, PA, United States

Natalie Blagowidow, MD,     Director, Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, United States

Joann Bodurtha, MD, MPH,     Professor of Genetic Medicine, Pediatrics and Oncology, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Alexander Bottini, MD,     Vitreoretinal Fellow, The Retina Institute, St. Louis, MO, United States

Takae M. Brewer, MD,     Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United States

Scott Brodie, MD, PhD,     Professor of Ophthalmology, New York University School of Medicine, New York University Langone Medical Center, New York University Eye Center, New York, NY, United States

Emily E. Brown, MGC, CGC,     Genetic Counselor, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Lynn Wein Bush, PhD, MS, MA

Faculty, Scientist, Bioethicist, Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States

Lecturer on Pediatrics, Harvard Medical School, Boston, MA, United States

Member of Faculty, HMS Center for Bioethics, Harvard Medical School, Boston, MA, United States

Russell J. Butterfield, MD,     Associate Professor, Division of Pediatric Neurology, Department of Pediatrics, University of Utah Health, Shriners Hospital for Children, Salt Lake City, UT, United States

Kirk Campbell, MD,     Professor of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Douglas K. Clemens, DMD,     Cross Keys Dental Associates, Baltimore, MD, United States

Virginia L. Corson, MS, CGC,     Genetic Counselor, Associate Professor, Gynecology & Obstetrics and Pediatrics (retired), Johns Hopkins University School of Medicine, Baltimore, MD, United States

Cheryl Cytrynbaum, MS, CGC

Genetic Counsellor, Department of Genetic Counselling, Project Investigator, Genetics and Genome Biology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

Lecturer, Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

Vaidehi Dedania, MD,     Assistant Professor of Ophthalmology, New York University School of Medicine, New York University Langone Medical Center, New York University Eye Center, New York, NY, United States

George A. Diaz, MD, PhD,     Professor, Department of Genetics and Genomic Sciences, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Harry C. Dietz, III, MD,     Investigator Howard Hughes Medical Institute, William S. Smilow Center for Marfan Syndrome Research, Victor A. McKusick Professor of Medicine and Genetics, Assistant Professor of Neurosurgery, Associate Professor of Medicine, Professor of Pediatrics, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Mary Beth Palko Dinulos, MD,     Associate Professor of Pediatrics and Pathology, The Geisel School of Medicine at Dartmouth, Section Chief of Genetics and Child Development, Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States

Christine M. Eng, MD,     Professor, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States

Charis Eng, MD, PhD

Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine, Chair and Director, Genomic Medicine Institute, Chair and Director, Center for Personalized Genetic Healthcare, American Cancer Society Clinical Research Professor, Cleveland Clinic Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States

Department of Genetics and Genome Sciences, Germline High Risk Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States

Audrey L. Fan, MS, CGC,     Cancer Genetic Counselor, Cancer Genetics and Genomics, Stanford Healthcare, Palo Alto, CA, United States

Clair A. Francomano, MD,     Professor of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States

Steven J. Frucht, MD,     Professor, Department of Neurology, The Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, New York University Grossman School of Medicine, New York, NY, United States

Jaya Ganesh, MD,     Associate Professor of Pediatrics, Department of Genetics and Genomic Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY, United States

Bruce D. Gelb, MD,     Director and Gogel Family Professor, Mindich Child Health and Development Institute, Professor of Pediatrics and Genetics and Genomic Sciences, Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Lediana Goduni, MD,     Retina Fellow, Bascom Palmer Eye Institute, Miami, FL, United States

Shen Gu, PhD,     Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States; Assistant Professor, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong S.A.R., China

Isha Gupta, MS, LCGC, HBSc,     Genetic Counselor, Igentify, New York, NY, United States

Randi J. Hagerman, MD,     Medical Director of the MIND Institute, Distinguished Professor, Endowed Chair in Fragile X Research, UC Davis Health System, Sacramento, CA, United States

Judith G. Hall, MD,     Professor Emerita, Medical Genetics and Pediatrics, University of British Columbia, Vancouver, BC, Canada

Julie Hoover-Fong, MD, PhD,     Professor of Genetic Medicine and Pediatrics, McKusick-Nathans Department of Genetic Medicine, Director, Greenberg Center for Skeletal Dysplasias, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Louanne Hudgins, MD,     Professor of Pediatrics, Division of Medical Genetics, Stanford University, Director, Perinatal Genetics, Lucile Packard Children's Hospital, Stanford, CA, United States

Ayuko Iverson, MD,     Assistant Professor, Department of Genetics and Genomic Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Ethylin Wang Jabs, MD,     Chair of the Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States; Adjunct Professor of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Adjunct Professor of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Cynthia A. James, PhD, CGC,     Assistant Professor, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Shama Jari, MD,     Prenatal Geneticist, Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, United States

Kim M. Keppler-Noreuil, MD,     Professor of Pediatrics, Division Chief of Genetics and Metabolism, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States

Lynne M. Kerr, MD, PhD,     Professor, Division of Pediatric Neurology, Department of Pediatrics, University of Utah Health, Shriners Hospital for Children, Salt Lake City, UT, United States

Amy Kimball, MS, CGC,     Genetic Counselor, Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, United States

Antonie D. Kline, MD,     Director of Clinical Genetics, Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, United States

Joel N. Kline, MD,     Professor and Vice-Chair, Division of Pulmonary, Critical Care and Occupational Medicine, Department of Medicine, University of Iowa School of Medicine, Iowa City, IA, United States

Amy Kritzer, MD

Attending Physician, Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States

Assistant Professor, Harvard Medical School, Boston, MA, United States

Michele P. Lambert, MD, MSTR,     Associate Professor of Pediatrics, Perelman School of Medicine at University of Pennsylvania, and Medical Director, Special Coagulation Laboratory, Director, Pediatric Platelet Disorder Program, Children's Hospital of Philadelphia, Philadelphia, PA, United States

Cheryl D. Lew, MD, MSEd, MS, HEC-C

Director, Pediatric Rare Lung Disease Program and Director, Home Mechanical Ventilation Program, Division of Pediatric Pulmonology and Sleep Medicine, Children's Hospital Los Angeles, Los Angeles, CA, United States

Clinical Professor of Pediatrics, Keck School of Medicine at University, Southern California, Los Angeles, CA, United States

Clinical Professor of Pediatrics, Emeritus Keck School of Medicine at University Southern California, Los Angeles, CA, United States

Shao-Tzu Li, MS, CGC,     Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore

Gretchen MacCarrick, MS, CGC,     Genetic Counselor, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Dena R. Matalon, MD,     Clinical Assistant Professor, Department of Pediatrics, Division of Medical Genetics, Associate Program Director, Medical Genetics Residency, Stanford University, Lucile Packard Children's Hospital, Stanford, CA, United States

Donna M. McDonald-McGinn, MS, CGC,     Chief, Section of Genetic Counseling, Clinical Genetics Center, 22q and You Center, The Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, United States; Department of Human Biology and Medical Genetics, Sapienza University, Rome, Italy

Francis J. McMahon, MD,     Chief, Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, United States

Kristin Meliambro, MD,     Assistant Professor, Icahn School of Medicine at Mount Sinai, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Rebekah A. Moore, MS, LGC

Genomic Medicine Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States

DDR Precision Medicine, AstraZeneca Pharmaceuticals, Gaithersburg, MD, United States

Brittney Murray, MS, CGC,     Genetic Counselor, Division of Cardiology, Johns Hopkins University, Baltimore, MD, United States

Tara Newcomb, MS, CGC,     Neuromuscular Genetic Counselor, Division of Pediatric Neurology, University of Utah Health, School of Medicine, Papillion, NE, United States

Joanne Ngeow, MBBS, MPH

Head, Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore

Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore

Jessica Ogawa, MD

Assistant Professor, Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, United States

Professor of Genetic Medicine, Pediatrics and Oncology, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Dhruv K. Patel, BSc,     Philadelphia College of Osteopathic Medicine, Philadelphia, PA, United States

Toni I. Pollin, MS, PhD, CGC,     Associate Professor, Medicine and Epidemiology and Public Health, Track Leader, Human Genetics, University of Maryland School of Medicine, Baltimore, MD, United States

Pankaj Prasun, MD,     Assistant Professor of Genetics and Genomics, Assistant Professor of Pediatrics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Maksym Puliaiev, MD

Fellow, Pulmonary and Critical Care Medicine, University of Iowa School of Medicine, University of Iowa Health Care, Iowa City, IA, United States

Pulmonary and Critical Care Medicine, MercyOne Healthcare System, Des Moines, IA, United States

Reed E. Pyeritz, MD, PhD,     William Smilow Professor of Medicine and Professor of Genetics, Emeritus, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Sonja A. Rasmussen, MD, MS,     Professor, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Giulietta Maria Riboldi, MD,     Instructor, Department of Neurology, The Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, New York University Grossman School of Medicine, New York, NY, United States

Scott M. Schecter, MD,     Assistant Professor, Division of Pulmonary and Critical Care Medicine, University of Virginia Health, Charlottesville, VA, United States

Angela E. Scheuerle, MD,     Professor, Department of Pediatrics, Division of Genetics and Metabolism, Professor, Department of Pathology, Division of Genetic Diagnostics, Director UTSW Rare Disease Center of Excellence, UT Southwestern Medical Center, Dallas, TX, United States

Stuart A. Scott, PhD

Professor, Department of Pathology, Stanford University, Stanford, CA, United States

Clinical Genomics Laboratory, Stanford Medicine, Palo Alto, CA, United States

Suma Shankar, MD, PhD,     Professor, Chief, Division of Genomic Medicine, Pediatrics & Ophthalmology, University of California Davis, Sacramento, United States

Anne Slavotinek, MBBS, PhD,     Professor of Pediatrics, Medical Genetics, Division Director, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States

Constance L. Smith-Hicks, MD, PhD,     Associate Professor of Neurology, Neurology and Developmental Medicine, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Rosalyn W. Stewart, MD, MS, MBA,     Professor, Internal Medicine and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, United States

Cristina Trandafir, MD

Assistant Professor, Division of Pediatric Neurology, Department of Pediatrics, University of Utah Health, Salt Lake City, UT, United States

Division of Pediatric Neurology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States

Vivian Narcisa Triano, MS, LCGC,     Genetic Counselor, Kaiser Permanente Northern California, North Valley Genetics, Sacramento, CA, United States

Hilary J. Vernon, MD, PhD,     Associate Professor of Pediatrics, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Melissa P. Wasserstein, MD,     Chief, Division of Pediatric Genetic Medicine, Professor of Pediatrics and Genetics, The Children's Hospital at Montefiore, The University Hospital for Albert Einstein College of Medicine, Bronx, NY, United States

Bryn D. Webb, MD

Assistant Professor of Genetics and Genomic Sciences, Assistant Professor of Pediatrics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Associate Professor, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States

Rosanna Weksberg, MD, PhD

Clinical Geneticist, Division of Clinical and Metabolic Genetics, Senior Associate Scientist, Genetics and Genome Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

Professor of Pediatrics and Molecular Genetics, Institute of Medical Science, University of Toronto, Toronto, ON, Canada

Bo Yuan, PhD

Assistant Professor, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States

Clinical Assistant Professor, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States

Laboratory Director, Department of Laboratories, Seattle Children's Hospital, Seattle, WA, United States

Foreword

At the start of my career, I was planning on becoming a geneticist. I was in graduate school earning my master's degree in genetics, and the cystic fibrosis gene had just been discovered. The polymerase chain reaction (PCR) was new and took hours to complete. The human genome project had begun. It seemed both portentous and full of potential. Soon thereafter, I was an eager medicine-pediatrics resident whose favorite book was Smith's Recognizable Patterns of Human Malformation. However, my career path changed and I became a primary care physician. Now, I am a practicing general internist and general pediatrician. In my daily life, understanding the effects of genetics on disease is undeniable, from the obvious genetic diseases, such as sickle cell anemia and cystic fibrosis, to the more complex disorders such as cardiovascular disease, asthma, diabetes, and cancer susceptibility. Genetics is everywhere and includes classic Mendelian inheritance as well as other mechanisms of inheritance and effects of phenotype (e.g., mitochondrial, sex-linked expression, mosaicism, incomplete penetrance, epigenetics, etc.). Patients are now solicited by private companies to learn their ancestry breakdown, genetic health risks with increasing frequency. There are recommendations for diagnosis of many disorders by genetic testing and determination of potential risks with genetic counseling. The field of genetics has evolved tremendously since my master's degree. My once facile knowledge is now passé.

Genomics in the Clinic is a must read to help understand the myriad genetic usages in today's practice and to help clinicians improve their communication with patients. This book reviews basic terminology, and applicability of genetics in prenatal diagnosis, cancer care, and prevention. Practitioners will find this book useful to understand the effects of genetics in clinical practice. The authors, Drs. Kline and Jabs, have been studying and practicing genetics for over 30 years and provide a practical and easy-to-understand guide through complex genetic patterns of inheritance and their applicability in practice.

Dr. Antonie Debra Kline is the Director of Clinical Genetics at The Harvey Institute for Human Genetics, Greater Baltimore Medical Center. She is a clinically active medical geneticist, board certified in Pediatrics, and Clinical Genetics and Genomics. She is the Chair of the Baltimore-Washington Genetics Group. Dr. Kline has studied the clinical characterization, growth and development, natural history, and aging of Cornelia de Lange syndrome. She has been a strong proponent of patient advocacy and is the Medical Director of the Cornelia de Lange Syndrome Foundation and nationally recognized for her exceptional work with this condition. She also has conducted research on the quality of life of individuals with Ehlers–Danlos syndrome and the natural history of the Alstrom and Au–Kline syndromes.

Dr. Ethylin Wang (Mimi) Jabs∗ is Mount Sinai Professor of Developmental Genetics in the Departments of Genetics and Genomic Sciences, Cell Developmental and Regenerative Biology, and Pediatrics at The Icahn School of Medicine at Mount Sinai. Dr. Jabs is a clinical geneticist who is board certified in Clinical Genetics, Clinical Cytogenetics, and Molecular Genetics. She is an educator and previously directed the Mount Sinai's ACMGE accredited Medical Genetics Residency and Fellowship Training Programs and a Primary Care Provider Education on Common Disease Genetics program funded by the National Institutes of Health. Her major research interests are in craniofacial disorders. She has authored more than 300 original articles, reviews, and chapters.

Their broad expertise combines with the clinical experience of multiple clinical geneticists and specialists to create an easy-to-read, highly relevant book. They review genetic terminology, the many heritable patterns, and explain techniques and methods of genetic testing and result interpretation. With this book, clinicians will understand everything from genetic screening in pregnancy and taking a family history of cancer, to the interpretation of genetic and genomic results and their management. They review the implications of direct-to-consumer marketing for genetic testing and ethical and psychosocial implications associated with genetic testing results. Their approach of using case-based examples to explain basic genetic concepts and complex genomics adds to the everyday relevance and enjoyment of this text. Readers will gain a clearer understanding of genetics and its influence on nearly all aspects of healthcare. A read of this book is essential for understanding, preventing, treating, and curing disease.

Rosalyn W. Stewart, MD, MS, MBA

Professor of Clinical Medicine

Departments of Internal Medicine and Pediatrics

Johns Hopkins University School of Medicine

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∗ Author EWJ was employed by Icahn School of Medicine at Mount Sinai at the time of writing the manuscript, but is currently employed by Mayo Clinic.

Acknowledgments

We would like to acknowledge those who significantly helped with this project. We greatly appreciate Erin Brittain for her editing and formatting of text, figures, tables, and references for the entire book. We also thank the following individuals for their review and suggestions on concepts, chapters, and cases for the book: Jennifer Billiet, Karen Brown, Emalyn Cork, Audrey Fan, Lisa Karger, and Lakshmi Mehta.

Chapter 1: Introduction

Ethylin Wang Jabs¹,∗, and Antonie D. Kline²     ¹Department of Genetics and Genomic Sciences, Department of Pediatrics, Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States     ²Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, United States

Abstract

The field of genetics and genomics is expanding rapidly, and clinical skills in genetics are needed in all aspects of medicine. The genetic community agrees that an understanding of the basic tenets and evolving concepts of genetics and genomics will improve healthcare throughout all disciplines. The overall goal of this book is to be used not only as a reference when managing patients with potential genetic conditions but also as instruction on the significant role that genetics and genomics are playing and will continue to play in understanding, preventing, treating, and curing disease in the future.

Keywords

Dominant; Epigenomics; Ethics; Genetic testing; Genetics; Genomics; Inheritance; Mendelian; Mitochondria; Mosaicism; Non-mendelian; Psychosocial; Recessive; Variant

Genetic concepts are ancient, mentioned in the hieroglyphics of ancient Egypt (2500–200 BCE) and in early bibles (4th century) (Rosner, 1969; Litwins, 1972; Scaiewicz and Levitt, 2015). The migration of the earliest humans before 2300 BCE from Africa to the rest of the world has been elucidated through genetic studies (Bergström et al., 2021). Most significantly, the work of Gregor Mendel (1822–1884) (Schacherer, 2016) points to the importance of genetic concepts in the outcome of not only an individual but also future generations. Nobel prize–winning research, with the discovery of the DNA structure, Sanger sequencing, polymerase chain reaction, and CRISPR, created tools instrumental in the development of genetics and genomics. Moreover, the Human Genome Project jumpstarted the genetic revolution with the completion of the first draft of the human genome sequence in 2001 (Venter et al., 2001; Lander et al., 2001). In the last decade, there has been an explosion of data with the use of diagnostic interventions of digital and imaging health tools and artificial intelligence, as well as innovative molecular and sequencing technologies.

The impact of these major historic milestones on gene discovery and genetic testing ultimately led to the recognition of clinical genetics and genomics as a specialty globally (Rimoin 2011; Zhang et al., 2014; Ferreira et al., 2017; Regier et al., 2017). Norway was the first country in recognizing medical genetics as a specialty in 1971, followed by other European countries, but not until 2011 was clinical genetics officially recognized as a European Union–wide medical specialty. In Brazil, the first medical residency program in medical genetics at the University of Sao Paulo was recognized in 1977, and medical genetics was recognized as a medical specialty by the Federal Council of Medicine in 1983. In South Africa, medical genetics was recognized as a subspecialty in medicine in 2007. The African Genomic Medicine Training Initiative was conceived in 2016 to develop knowledge and skills and improve competency in genomic medicine in nursing (Nembaware et al., 2019). In China, medical genetics was formally recognized as a clinical specialty in 2014 (Sun et al., 2019). There are, however, relatively few training programs for residents in clinical genetics and allied health professionals in genetic counseling in most of Latin America, South America, Asia, and Africa to date.

In the United States, both the American Board of Medical Specialties (ABMS) (http://www.abms.org) and the Council on Medical Education of the American Medical Association independently approved acceptance of Clinical Genetics as a new board within the ABMS in 1991. The ABMS now approves the certification of an individual with an MD and/or a PhD in the areas of clinical genetics and genomics, medical biochemical genetics, clinical biochemical genetics, and laboratory genetics and genomics (combining the former areas of clinical cytogenetics and genomics, and clinical molecular genetics and genomics) (http://www.abmgg.org). The American Board of Genetic Counselors was incorporated in 1993 (https://www.abgc.net), establishing their own board for certification and the accreditation of graduate level training programs for a Master's degree as well as a PhD in Genetic Counseling. With the use of genetic technologies in diagnostics, molecular training certification also can be obtained through other boards at the doctorate level, such as molecular genetic pathology from the American Board of Pathology.

Although the discipline of genetics in the clinical setting is relatively young compared to other major clinical disciplines, its principles are applicable in all aspects of medicine. The cornerstone of genetics is the concept of Mendelian inheritance, named after Mendel's work (Schacherer, 2016). He showed by cross-breeding peas of two distinct color traits (yellow and green) that the next generation would have one of these colors in a ratio of one green and three yellow peas or all only in the yellow color. He termed the yellow peas as having factors that were dominant and the green peas as having recessive factors. We now know these factors to be genetic variants. Mendelian conditions, including sickle cell disease and cystic fibrosis, long have been classic examples for the study of clinical genetics. Although much of genetics is represented by rare syndromes, collectively these conditions are abundant. In turn, non-Mendelian inheritance encompasses complex diseases secondary to disruptions in the regulatory networks of multiple genes and environmental factors. Examples of complex diseases include heart disease, cancer, and psychiatric disorders.

Clinical medicine essentially comprises all conditions along a spectrum, with those at one end caused by a variation in a single gene of strong effect (Mendelian) and at the other end caused by the collective contribution of small effects of multiple genes (non-Mendelian). Most pathogenicity in medicine can be, at least in part, due to genetic and genomic variation. All conditions, even those due to a single gene variant, are modified by the effects from all of the other genetic information in our cells as well as environmental exposures, leading to variability in phenotypic outcome. Our collective DNA varies by about one-hundredth of one percent. No two individuals have exactly the identical genomic make-up. Thus, no two individuals have the same phenotype, severity, and outcome of a disease. Even monozygotic twins do not have the same genomes, transcriptomes, or epigenomes (Jonsson et al., 2021; Koch, 2021). The precision in quantitating phenotypes and associating genotypes in patients has ushered in the era of personalized medicine (Topol, 2014).

Genetics and genomics have moved to the forefront of practicing medicine and are being integrated into all clinical disciplines. The implementation of novel technologies of next-generation sequencing now enables sequencing an individual's genomic DNA from a very small amount of sample, a variety of sources, and more rapidly at lower and lower cost. Thus, the combination of detailed phenotyping and omic sequencing (i.e., global analysis such as genomics, proteomics, and metabolomics) in large data sets has fostered the growth of genomic medicine, especially in the areas of genetic syndromes, prenatal genetics, pharmacogenomic testing, and cancer genomics.

Newer research discoveries of non-Mendelian concepts of mosaicism, mitochondrial genetics, epigenetics, transcriptomics, and systems biology highlight that the interpretation of genomics as well as other omic data are rapidly evolving and not always straightforward. Careful interpretation of DNA sequences is challenging, and ethical use of this information is important. Because of this, those empowered to care for patients using omic data must be educated and understand their benefits as well as their limitations. A negative result on a genetic test does not necessarily imply lack of genetic disease; it merely means that a positive result may not have been found yet due to the limitations of the test and/or our current inability to conclusively interpret the sequence results. A variant of unknown clinical significance may be a common result on genetic testing but also may be resolved by reanalysis when new published information becomes available from standardized cohort or population studies (https://www.ncbi.nlm.nih.gov/clinvar). Lastly, a positive result does not necessarily have clinical utility, especially if a genetic diagnosis is not preventable or treatable, as in most complex disorders such as psychiatric conditions. Providers need to weigh whether giving a presymptomatic positive result to an individual truly does no harm, as in Huntington disease with no current treatment but with potential of clinical trials, or a positive predictive result for some breast cancers, with surgical treatment and increased risks for additional malignancies, but no preventative measures.

Furthermore, there are far fewer clinical geneticists than needed, even when combined with PhD geneticists. Results from United States surveys estimate that there are approximately two clinical geneticists for every million people (Maiese et al., 2019; Jenkins et al., 2021; https://www.gao.gov/assets/710/708545.pdf). There are estimated 1.3–1.5 genetic counselors for every 100,000 individuals in Canada and United States (Costa et al., 2021). In addition, genetic counseling is a profession that is projected to grow 21% from 2019 to 2029, much faster than the average for all occupations of 7% (https://www.bls.gov/ooh/healthcare/genetic-counselors.htm). Nongenetic healthcare providers have begun to order genetic and genomic tests and deliver care based on these results. Patients are ordering their own genetic kits and are asking for help in interpretation from their primary care doctors. Thus, there is a need to educate more healthcare professionals, not just clinical or laboratory genetic trainees, to understand the principles of genetics and genomics, how they can be applied in the clinic, and when to refer to clinical genetics.

The nuances of a genetic evaluation and the various genetic technologies are beyond the scope of what is taught in many healthcare training programs (Campion et al., 2019). Knowledge of criteria for an appropriate genetics referral and having the ability to set expectations, to understand basic testing and molecular nomenclature, to interpret test results, to communicate implications of the results for the individual and other family members, to provide management and treatment, and to grasp the ethical and psychosocial implications of genetics and genomics in medicine are becoming essential clinical skills for the average healthcare provider. The new technologies can be incorporated into primary care. Some centers are testing all comers for genome variation, building evidence for next-generation sequencing in the context of routine primary care (Peterson et al., 2019). Other areas of medicine will consider some form of genetic testing, evaluation or treatment likely in all patients in the not-so-distant future, both for preventative and for pathologic reasons. Standardization for such testing is developed in some cases but not available for many clinical scenarios. Nongeneticists may find aspects of this book a useful reference prior to explaining the topic to their patients.

This book translates the salient concepts of clinical genetic care and testing into basic principles for nongenetic physicians, geneticists in training, and other healthcare professionals. It should be relevant within all practices of medicine. Chapters explain genetic concepts for all categories of care, from preconception through aging, of clinical genomics relevant to both Mendelian and complex disorders. Genetic issues in psychiatry are described in detail as an example of the latter. Direct-to-consumer testing and relevant concepts are reviewed, as this is a newer area of inquiry targeted at consumers. Likewise, the topic of ethical issues is introduced, as the potential for these increases when discussing genetic basis for disease and testing. More than 100 cases are presented that are representative of common clinic visits with typical presentations of concern to the nongenetic practitioner. When to consider a referral to a geneticist, and the recommended evaluations, workup, caveats, outcome, and diagnosis of each case, as well as implications for family members are described as guidelines. The lay language and accompanying figures of the final chapter can be used by healthcare providers to effectively communicate complicated concepts and types of tests and results to patients and their families. The hope is that appropriate genetic testing will be accessible to diverse populations and implemented to avoid disparity, stigmata, and loss of confidentiality, while being provided equitably and with inclusivity. With recent technological advances in genetic and genomic testing, a book for this purpose is essential to prepare clinicians for the new age of precision medicine with application of individualized management and treatment, with gene therapy and new molecular therapeutics on the horizon. The editors and authors intend for the readers to utilize Genomics in the Clinic as a reference guide, and also to enjoy the stories behind the concepts and appreciate the complex challenges and the nuances in providing the best clinical genetics and genomics care.

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∗ Author EWJ was employed by Icahn School of Medicine at Mount Sinai at the time of writing the manuscript, but is currently employed by Mayo Clinic

Chapter 2: Basic Principles of Genetics and Genomics

Shen Gu¹,², Bo Yuan¹,³, Ethylin Wang Jabs⁴,∗, and Christine M. Eng¹     ¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States     ²School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong S.A.R., China     ³Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States     ⁴Department of Genetics and Genomics Sciences, Department of Pediatrics, Department of Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Abstract

The basis of genetics and genomics are the units of heredity including all chromosomes and genes that instruct cells of our body how to function. Many different kinds of changes in chromosomes, DNA, genes, and proteins lead to diversity and disease and can be inherited in an autosomal, sex-linked, mitochondrial, or multifactorial fashion. This chapter will define the key principles of genetic and genomics as a foundation to understanding how variation in our DNA and its inheritance can cause disease.

Keywords

Autosome; Chromosome; DNA; Dominant, recessive, and X-linked inheritance; Epigenome; Exon; Gene; Genetic heterogeneity; Genome; Intron; Mitochondrion; Mosaicism; Penetrance; Phenotypic variability; Regulatory region; Repeat sequence; RNA

The human genome is composed of all the chromosomes or DNA in each cell of an individual. Human DNA is present in the cell nucleus and cytoplasm organelles, the mitochondria. Our understanding of the complex nature of DNA, genetics, and genomics has evolved over time through molecular discoveries driven by sequencing technologies. Healthcare workers must have knowledge of the basic principles of genetics and genomics in order to understand how to evaluate and diagnose genetic disorders, order appropriate tests, and interpret results. More importantly, comprehension of these principles enhances the ability of healthcare teams to communicate effectively genetic and genomic information to patients and their families. This chapter defines normal and common abnormalities in chromosomes, DNA, RNA, genes, coding and noncoding regulatory sequences, repeat sequences, mitochondria, and the epigenome found in individuals and populations. These mechanisms serve to explain various modes of inheritance of genetic disorders including Mendelian, autosomal, X-linked, mitochondrial, and multifactorial inheritance, as well as concepts of mosaicism, genetic heterogeneity, phenotypic variability, penetrance, and modifying factors.

2.1. Chromosome Structure and Function

Chromosomes in the nucleus are basic units of inheritance in the form of threadlike complexes that are primarily composed of deoxyribonucleic acid (DNA) and proteins including histones (Fig. 2.1) (Therman and Susman, 1993). The DNA–protein complex is referred to as chromatin. Chromosomes are present in all nucleated cells of the human body, so they are not present in mature red blood cells and cornified cells of the skin, hair, and nails that do not have a nucleus, as well as in mature hair cells that do not contain nuclear DNA.

Figure 2.1  Chromosome structure. Chromosomes are composed of the DNA double helix of ∼2 nm in diameter that is wound around nucleosomes, a protein complex formed from histone octamers, each with ∼140 base pairs (bp) of DNA and of ∼10 nm in size. The structure is condensed further into chromatin fibers with each loop containing ∼100,000 bp and of ∼30 nm in diameter that are looped to form the compact chromosome. Courtesy: National Human Genome Research Institute, https://www.genome.gov/genetics-glossary/histone.

Normally there are 46 individual chromosomes or 23 pairs of chromosomes (diploid set of chromosomes, 2n with n = 23 chromosomes) in the nucleus of human somatic cells. Twenty-two pairs are autosomal chromosomes and one pair consists of the sex chromosomes, either two X chromosomes in females or one X and one Y chromosome in males. In human gametes, there are 23 individual chromosomes (haploid set of chromosomes, 1n) and with fertilization, the chromosomes from the egg and sperm join to form the first cell of a zygote with 46 chromosomes or 23 pairs of chromosomes (2n). These are homologous pairs of chromosomes or the same chromosomes, one from the mother and one from the father. Chromosomes change in shape and function during the cell cycle as they undergo replication, segregation, and division when a single cell generates two daughter somatic cells during mitosis or four gametes during meiosis.

2.1.1. Mitosis

During mitosis or the one cell division process of somatic cells, 46 chromosomes are in their least condensed state during the synthesis phase (S phase) of interphase when they unwind in order to undergo replication (Therman and Susman, 1993). Each of the 46 chromosomes with one chromatid is duplicated to consist of two chromatids (2n 4c, with c = 23 chromatids). Chromosomes then become more condensed from the prophase and prometaphase to metaphase of the mitotic phase (M phase) when the duplicated homologous chromosomes are aligned along the metaphase plate to prepare for cell division. Chromosomes are held together at the centromere, a specialized structure where spindle fibers attach to mediate their proper movement during cell division. During anaphase and telophase the chromosomes separate so that when the parent cell divides into two daughter cells, each receives one chromatid of the 46 chromosomes (2n 2c). Thus, the process of mitosis creates two somatic cells with 46 chromosomes, each with 46 chromatids, the same number that was present in the original parent cell (Fig. 2.2).

2.1.2. Meiosis

During meiosis or the two cell division process of gametogenesis, oogenesis, or spermatogenesis, 46 chromosomes undergo replication (2n 4c). During prophase I, the chromatids from homologous chromosomes undergo synapsis, when their DNA can undergo crossing over (Therman and Susman, 1993). The chromatids of homologous chromosomes can exchange chromosomal DNA segments, or undergo recombination. These recombined chromatids are not identical to their parental chromatids. With the first cell division, or reduction division, the homologous chromosomes separate so that there are now 23 chromosomes each with two chromatids in two new daughter cells (1n 2c). With the second division, the two chromatids separate so that there are 23 chromosomes each with one chromatid in four new daughter cells (1n 1c). Thus, the process of meiosis creates four gametes, sperms, or eggs, each with 23 chromosomes with 23 chromatids that may not be identical in DNA content because of recombination, allowing for variation among offsprings (Fig. 2.2).

Figure 2.2  Mitotic and meiotic cell cycles. At the top in mitosis, diploid cells replicate chromosomes and segregate sister chromatids so that diploid daughter cells are produced. At the bottom in meiosis, two chromosome-segregation phases, meiosis I and meiosis II, follow a single round of DNA. During meiosis I, homologous chromosomes (shown in red and blue) undergo crossing-over and then segregate to opposite poles. During meiosis II, sister chromatids then segregate to opposite poles that result in the formation of nonidentical haploid gametes. Source: MHCC Biology 112: Biology for Health Professions, Section 80, Comparing Meiosis and Mitosis, OpenStax, Licensed under CC BY 4.0, https://mhccbiology112.pressbooks.com/chapter/comparing-meiosis-and-mitosis/. Modified from the original.

2.1.3. Karyotype

Karyotype is a microscopic image of an individual's chromosomes (Gersen and Keagle, 2011; Barch et al., 1997). During prometaphase and metaphase of the M phase, chromosomes are in a condensed state when it is easiest to visualize them under the microscope. The normal male karyotype is designated 46,XY and normal female karyotype is 46,XX, indicating the total number of chromosomes and the sex chromosomes. Chromosomes are different in size and shape (Fig. 2.3). The largest chromosome is numbered 1 and the smaller chromosomes are numbered 21 and 22. The chromatids constrict at the centromere giving a waistlike appearance at the middle of metacentric chromosomes, at an asymmetric position of submetacentric chromosomes, and near one end of acrocentric chromosomes. Generally, the large chromosomes are metacentric in shape such as chromosome 1, while the middle-sized chromosomes are submetacentric and smaller chromosomes 13, 14, 15, 21, and 22 are acrocentric. The centromere location defines two arms of the chromosome, referred to as the p or short and q or long arms. Thus, the acrocentric chromosomes have the smallest P arms. The two ends of the linear chromosomes are referred to as telomeres. Of note, the X is the largest submetacentric and the Y is a small acrocentric chromosome.

For karyotype analysis, chromosomes are stained to produce a banding pattern, with dark and light bands to define subregions of the chromosome. The number of banded regions of a chromosome depends on how condensed the chromosomes are. High-resolution banding used in clinical cytogenetic laboratories captures the chromosomes at the prophase to prometaphase stage and displays a total of 550–800 bands (Fig. 6.1). Bands are numbered on the P or q arms with the lower numbers near the centromere and the higher numbers near the telomeres (Simons et al., 2013). For example, band 1p36.2 is on the chromosome 1 short arm within band 36 at subband 2. Band 8q21.1 is on the chromosome 8 long arm within band 21 at subband 1. Band 8q21.1 is closer to the centromere and farther from the telomere of the chromosome 8 long arm than band 8q24.2.

Figure 2.3  Karyotype of normal human chromosomes. Ideogram showing G-banding (Giemsa staining) patterns of human metaphase chromosomes of a normal male, 46,XY. Chromosomes are noted by numbers 1–22, X and Y in blue . Centromeres are indicated by the dark gray regions with a dash separating the short ( P ) arms from the long (q) arms. Bands and subbands are numbered to the left in black . Reprinted from Human Genes and Genomes, Leon E. Rosenberg and Diane Drobnis Rosenberg, Chromosome Abnormalities, Fig. 11.2, Copyright 2012, with permission from Elsevier.

2.2. Chromosome Variation

The intricate processes of cell division and chromosome replication and segregation into daughter cells are usually precise and tightly regulated, yet errors can occur. Specifically, dysregulated meiosis producing a gamete with a chromosomal abnormality results in an abnormal conceptus, generating a constitutional abnormality that is present from conception and involves cells of the entire body (Gardner et al., 2012).

2.2.1. Chromosomal Aberrations

Variations in chromosomes can be in number or structure. Change in number can occur by the loss of an entire set of chromosomes, the gain of one or more complete sets of chromosomes, or the addition or loss of all or part of a chromosome. Each of these conditions is a variation on the normal diploid number of chromosomal material. The structure of chromosomes may change in shape and rearrangement that is unbalanced with loss or gain of DNA material or balanced with no apparent deletion, duplication, or insertion.

Abnormal Ploidy

A chromosome complement with an abnormal chromosome number that deviates from the normal diploid 46 is defined as heteroploidy. Aneuploidy and polyploidy have been observed in recognized conceptions and/or affected live births.

Aneuploidy is the presence of an abnormal number of chromosomes other than the normal cell number of 46, not including a difference of complete set(s) of chromosome homologs as seen in polyploidy cases. It is the most common type of human chromosome disorder, observed in at least 5% of clinically recognized conceptions. It could be trisomic (2n + 1 = 47) or monosomic (2n − 1 = 45), with monosomies more deleterious than trisomies. Except for monosomy X (Section 11.7.5), complete monosomies are not viable, while complete trisomies are viable for chromosome 13, 18, 21, X, and Y (Table 2.1, Sections 11.1.5, 11.1.3, 11.13.2).

Full aneuploidy has been attributed to meiotic nondisjunction in the great majority of situations (Fig. 2.4). Nondisjunction is defined as the failure of homologous chromosomes to segregate properly at cell division, and it could happen during either meiosis I or II division. Following the meiotic nondisjunction errors, the conceptus upon fertilization would be either trisomic or monosomic, assuming the other gamete to be normal.

Down syndrome (DS) is the most common and well-known chromosome disorder, characterized by a constellation of clinical findings including distinct facial features, moderate intellectual disability, congenital heart defects, and other recognizable phenotypes. Approximately 95% of DS is due to full trisomy 21, with maternal nondisjunction at the first meiotic division being the predominant cause, and advanced maternal age is a known risk factor (Sections 4.2.2, 11.1.3, 11.13.2).

Polyploidy is the state of more than two sets of paired homologous chromosomes seen in normal human cells (2n chromosomes = 46). Triploidy (3n = 69) and tetraploidy (4n = 92) have been observed