Self-assessment Questions for Clinical Molecular Genetics

Haiying Meng

• Publisher: Academic Press
• Year: 2019
• Print ISBN: 9780128099674
• eBook ISBN: 9780128099681
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Review Questions of Clinical Molecular Genetics presents a comprehensive study guide for the board and certificate exams presented by the American College of Medical Genetics and Genomics (ACMG) and the American Board of Medical Genetics and Genomics (ABMGG). It provides residents and fellows in genetics and genomics with over 1, 000 concise questions, ranging from topics in cystic fibrosis, to genetic counseling, to trinucleotide repeat expansion disorders. It puts key points in the form of questions, thus challenging the reader to retain knowledge. As board and certificate exams require knowledge of new technologies and applications, this book helps users meet that challenge.- Includes over 1, 0000 multiple-choice, USMLE style questions to help readers prepare for specialty exams in Clinical Cytogenetics and Clinical Molecular Genetics- Designed to assist clinical molecular genetic fellows, genetic counselors, medical genetic residents and fellows, and molecular pathologist residents in preparing for their certification exam- Assists trainees on how to follow guidelines and put them in practice

Chapter 1

General Molecular Genetic Knowledge

Abstract

Clinical laboratories use molecular genetic techniques to analyze DNA, RNA, or proteins for diagnosis, risk assessment, possible prognosis, progress monitoring, and prospective therapy treatments. In the 1980s, clinical laboratories primarily used the molecular genetic techniques to analyze variants for diagnosis. The earliest assays were targeted to a few disorders such as sickle cell disease and cystic fibrosis. These early molecular diagnoses often involved indirect mutation detection through linkage analyses, which is extremely labor-intensive and required large samples of peripheral-blood from patients.

Keywords

DNA (gDNA, cDNA, mtDNA); RNA (mRNA); tRNA; microRNA; snRNA; 9hnRNA); short tandem repeats (STRs); single nucleotide polymorphisms (SNPs); deletion; duplication; acquired; constitutional; silent mutation; missense; nonsense; frameshift; in-frame; nonstop mutation; splice-site mutation; haplotype; genotype; allele; Mendelian inheritance; common disorders; autosomal dominant; autosomal recessive; mitochondrial inheritance; loss of function; gain of function; haploinsufficiency; dominant negative; genetic heterogeneity; locus heterogeneity; allelic heterogeneity; pleiotropy; epistasis; incomplete penetrance; variable expression; LOD score; relative risk; positive predictive value; negative predictive value; sensitivity; specificity; founder effect; heterozygote advantage; phenocopy; positive selection; negative selection; Knudson hypothesis; proto-oncogene; tumor suppressor gene; genetic distance; methylation; cell cycle; prevalence; incidence; primer; probe; PCR; capillary electrophoresis; multiplex ligation-dependent probe amplification (MLPA); Sanger sequencing; next generation sequencing (NGS); reading deep; sequencing-by-synthesis

Clinical laboratories use molecular genetic techniques to analyze DNA, RNA, or proteins for diagnosis, risk assessment, possible prognosis, progress monitoring, and prospective therapy treatments. In the 1980s, clinical laboratories primarily used the molecular genetic techniques to analyze variants for diagnosis. The earliest assays were targeted to a few disorders such as sickle cell disease and cystic fibrosis. These early molecular diagnoses often involved indirect mutation detection through linkage analyses, which is extremely labor-intensive and required large samples of peripheral-blood from patients.

In 1986, Mullis et al. discovered the polymerase chain reaction (PCR), which revolutionized molecular diagnosis. Assays in use previously were quickly modified to incorporate the use of PCR-amplified DNA.¹ During the 1990s, the identification of more genes in the human genome and the invention of Sanger sequencing led to the emergence of a distinct field of molecular and genomic laboratory medicine. PCR-Sanger became the most common technique for the analysis of many genetic disorders in clinical molecular laboratories. In 2003, the near completion of the Human Genome Project exponentially heightened the importance of molecular genetics in laboratory medicine. The 1000 Genome Project accumulated genetic information from the general population for variations in classification.

Nowadays, next-generation sequencing (NGS) incorporated with automated large-scale sequence analysis appears to be more and more essential for the diagnosis of many genetic disorders in clinical molecular laboratories. The growing role of bioinformatics brought the advanced mathematical and computing approach into clinical molecular genetic practice. The discovery of circulating cell-free DNA (cfDNA) revolutionized prenatal genetic testing and tumor screening/monitoring. Clinical molecular genetic practice offers the prospect of personalized medicine.

As the title of this chapter suggests, we are going to review basic genetic knowledge through the most commonly used assays in clinical molecular genetic laboratories, including NGS, from a historical point of view. It seems to be boring for professionals. Hopefully, it will refresh some memories for the following chapters.

Questions

1. 1. A pediatric geneticist saw a 12-month-old boy for tetralogy of Fallot, cleft palate and lip, recurrent infection, and developmental delay. Since the American College of Medical Genetics and Genomics (ACMGG) recommends chromosome microarray analysis (CMA) as the first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies, the geneticist ordered CMA for this patient. Which one of the following specimens has highest quality of DNA, and most suitable for CMA?
   1. A. 1 mL of blood in a green top tube
   2. B. 1 mL of blood in a purple (lavender) top tube
   3. C. 1 mL of saliva
   4. D. 0.5–1 cm diameter of a dried blood spot
   5. E. 10 mm² of formalin-fixed tissue
2. 2. A courier picked up a whole-blood sample (EDTA, lavender) from an outreach blood-draw station for BCR/ABL1 quantitative testing at the main hospital. Which one of the following conditions is preferred for the transportation of this sample?
   1. A. Ambient
   2. B. On ice packs
   3. C. In dry ice
   4. D. None of above
3. 3. A courier picked up a whole-blood sample (lavender) from an outreach blood-draw station for JAK2 V617F quantitative testing at the main hospital. Which one of the following conditions is preferred for the transportation of this sample?
   1. A. Ambient
   2. B. On ice packs
   3. C. In dry ice
   4. D. None of the above
4. 4. A technologist in a clinical molecular genetic laboratory extracted nucleic acid from a peripheral-blood sample for BCR-ABL1 quantitative testing. Which one of the following conditions is preferred for storage of the extracted nucleic acid before the test is performed?
   1. A. Ambient
   2. B. Refrigerated (4°C)
   3. C. −20°C
   4. D. None of the above
5. 5. A technologist in a clinical molecular genetic laboratory extracted nucleic acid from a peripheral-blood sample for JAK2 V617F quantitative testing. Which one of the following conditions is preferred for storage of the extracted nucleic acid before the test is performed?
   1. A. Ambient
   2. B. Refrigerated (4°C)
   3. C. −20°C
   4. D. −80°C
   5. E. None of the above
6. 6. As a clinical molecular laboratory director, you led a continue education session for the technologists about quality control for PCR reaction. At the end of the presentation, a junior technologist asked how to tell whether a PCR result is false negative. In which one of the following situations would the results on the tested specimens be considered as false negative for amplification?
   1. A. The positive control is negative.
   2. B. The positive control is positive.
   3. C. The negative control is positive.
   4. D. The negative control is negative.
7. 7. As a clinical molecular laboratory director, you led a cont...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• About the Author
• Preface
• Acknowledgments
• Chapter 1. General Molecular Genetic Knowledge
• Chapter 2. Regulations From Oversight Agencies
• Chapter 3. Molecular Genetic Nomenclature
• Chapter 4. Disorders of Unstable Repeat Sequences
• Chapter 5. Cystic Fibrosis
• Chapter 6. Nonneoplastic Hematological Disorders
• Chapter 7. Oncology—Constitutional
• Chapter 8. Oncology—Acquired
• Chapter 9. Lysosomal Storage Disorders
• Chapter 10. Neuromuscular Disorders
• Chapter 11. Prenatal, Newborn Screen, and Metabolic Disorders
• Chapter 12. Other Common Genetic Syndromes
• Chapter 13. Pharmacogenetics
• Chapter 14. Genetic Counseling—Introduction
• Index