Perinatal Genetics

Mary E Norton, Jeffrey A. Kuller, Lorraine Dugoff

• Publisher: Elsevier
• Year: 2019
• ISBN:
  9780323530965
• Topic: Medicina
• Subtopic: Ginecología, obstetricia y partería

Get a quick, expert overview of the fast-changing field of perinatal genetics with this concise, practical resource. Drs. Mary Norton, Jeffrey A. Kuller, Lorraine Dugoff, and George Saade fully cover the clinically relevant topics that are key to providers who care for pregnant women and couples contemplating pregnancy. It's an ideal resource for Ob/Gyn physicians, maternal-fetal medicine specialists, and clinical geneticists, as well as midwives, nurse practitioners, and other obstetric providers.

• Provides a comprehensive review of basic principles of medical genetics and genetic counseling, molecular genetics, cytogenetics, prenatal screening options, chromosomal microarray analysis, whole exome sequencing, prenatal ultrasound, diagnostic testing, and more.
• Contains a chapter on fetal treatment of genetic disorders.
• Consolidates today's available information and experience in this important area into one convenient resource.

Chapter 1

Principles of Genetics and Genomics

Joseph R. Biggio Jr. MD, MS

Abstract

Few areas in medicine have seen such rapid and dramatic advances in knowledge and technology as the field of genetics has over the past two decades. Genetics is no longer a field of rare diseases that only a few need to understand. With our rapidly growing understanding of the human genome, it is clear that there is a genetic underpinning to almost all medical conditions, structural abnormalities, and functional disorders. With the increasingly commonplace application of genetic and genomic principles to the diagnosis and management of many disorders, it is essential that all obstetric providers develop an understanding of the basic principles underlying these revolutionary changes.

Keywords

Genomic disorders; Mutations; Patterns of inheritance; Pedigree

Introduction

Few areas in medicine have seen such rapid and dramatic advances in knowledge and technology as the field of genetics has over the past two decades. Breakthroughs such as the mapping of the human genome and technological advancements enabling rapid gene sequencing have not only greatly enhanced our understanding of common and uncommon disorders but also changed the way the medical profession approaches the diagnosis, prevention, and treatment of disease. In the field of obstetrics and gynecology, the ability to map fragments of cell-free placental DNA to specific chromosomes has led to highly accurate screening tests for common aneuploidies. Similarly, the use of genomic hybridization techniques has enabled the detection of small variations in genomic composition below the resolution of conventional karyotype that are now known to be responsible for a variety of genomic disorders. The impact of precision medicine remains fledgling in the field of perinatal medicine, but with its growing utility in other areas of medicine, especially with regard to targeted pharmacologic therapy, it is very likely that we will see similar application of precision medicine to perinatal medicine in the coming years.

Genetics is no longer a field of rare diseases that only a few need to understand. With our rapidly growing understanding of the human genome, it is clear that there is a genetic underpinning to almost all medical conditions, structural abnormalities, and functional disorders. Modern genetics and genomics provide the medical professional deeper insight and more information into medical disorders with far less material and less invasive approaches than ever before. With the increasingly commonplace application of genetic and genomic principles to the diagnosis and management of many disorders, it is essential that all providers develop an understanding of the basic principles underlying the field of genetics.

What Is the Difference Between “Genetics” and “Genomics”?

The field of medical genetics focuses on the contribution of changes (or “variants”) in individual genes to human variation and disease. In contrast, genomics focuses on all of the genes, called the genome, and how multiple genes interact and function to result in either a state of health or disease. The study of genomics has only become possible recently with advances in DNA sequencing technology.

How Does the Structure and Organization of Genes Affect the Regulation of Gene Function?

The cell nucleus and the mitochondria contain all of the genes in humans. The 46 nuclear chromosomes—22 paired autosomes and 2 sex chromosomes—contain the majority of this genetic material. Although the Y chromosome contains only a few genes in addition to those responsible for male sexual differentiation and development, the X chromosome has a number of genes that are integral to normal development and physiologic function for both sexes.

There are approximately 3 billion base pairs of DNA per human genome, and DNA length is normally measured in kilobases (1000 bases, kb) or megabases (1,000,000 bases, Mb). Humans have between 20,000 and 23,000 genes—fewer than the 40,000 postulated before the completion of the Human Genome project; this represents only approximately 10%–15% of the total complement of the DNA.

Each gene contains the information necessary for production of an intact protein and is composed of sequences of DNA that contain regulatory elements and coding regions (Fig. 1.1). Four purine and pyrimidine bases are the building blocks for each gene and ultimately determine the protein sequence produced. Exons are the segments of coding DNA that are transcribed into messenger RNA (mRNA), which then serves as the template from which the amino acid sequence, and ultimately the protein structure, is determined. A series of three nucleotide base pairs, termed a codon, determines the amino acid to be added to the building protein chain as the mRNA is translated. Because there are 64 possible codons and only 20 amino acids, there is redundancy with many amino acids coded for by multiple codons.

Introns are noncoding regions within the gene that separate exons. Although introns were once thought to be “junk” DNA, it is now known that DNA sequences within the introns play a role in gene regulation and expression. For example, some genes may encode multiple proteins with the ultimate protein product determined by how the exons are spliced together, a process controlled by the DNA sequences within the introns. Other noncoding regulatory regions are located outside the coding region of the gene in the upstream 5′ untranslated region and the downstream 3′ untranslated region. In addition to these DNA segments that are actually transcribed into the initial mRNA transcript, a number of other DNA regulatory elements that allow for binding of molecules involved in control of transcription are located in the 5′ upstream area, e.g., promoter region, or TATA box.

The complexity of these regulatory processes is far more involved than previously thought, and the role of genetic variation in these regulatory elements and in the molecules they bind in human disease is only beginning to be understood. In addition to changes in the DNA sequence affecting gene transcription, other modifiable processes can also alter gene expression. Epigenetic changes, such as DNA methylation and histone acetylation, control gene transcription by preventing or facilitating binding of key molecules involved in DNA transcription. Such changes appear to play a role in tissue-specific and time-specific gene expression.

What Are the Types of DNA Sequence Variation That Can Occur?

Although greater than 99% of DNA is identical from one individual to the next, genetic variation occurs at various sites throughout the genome. The different variants that exist at any one site or locus are termed alleles . Polymorphisms are differences in DNA that occur in the population throughout the genome and can consist of single nucleotide changes or duplications or deletions of larger segments of DNA. Most polymorphisms are benign and do not result in alteration of protein function, although some polymorphisms have been associated with altered protein function (e.g., factor V Leiden). Mutations are changes in DNA sequence that result in altered protein production, structure, or function.

FIG. 1.1 The structure of a protein-coding gene demonstrating the regulatory regions as well as the protein-coding regions with the introns and exons that are transcribed into mRNA. The mRNA molecule undergoes modification to a mature molecule, which is then translated to create a protein.
Retrieved from WikiMedia Commons at https://commons.wikimedia.org/wiki/File:Gene_structure_eukaryote_2_annotated.svg on March 4, 2018. Shafee T, Lowe R. Eukaryotic and prokaryotic gene structure. WikiJ Med. 2017; 4(1). ISSN 20024436. https://doi.org/10.15347/wjm/2017.002. posted on April 9, 2015.

Single nucleotide polymorphisms (SNPs) are the replacement of a single base for another in the DNA sequence. SNPs are the most common form of genetic variation and occur approximately every 200–300 base pairs. Such substitutions typically have no significant effect on gene function, but depending on the location, significant effects on protein production or function can be seen. The distinction between a polymorphism and a mutation is to some degree a matter of semantics, but historically polymorphisms have largely been viewed as benign genetic changes that are found in the population more commonly than mutations are thought to occur.

Nonsense mutations result when the base substitution results in a change that alters the codon for an amino acid to one for a stop codon, leading to premature termination of protein synthesis from the mRNA molecule. Missense mutations occur when the SNP changes the codon for one amino acid to that for another amino acid; depending on the amino acid change, the structure and function of the protein may be changed. Splice site mutations are those that occur at an intron-exon boundary and affect the normal splicing of mRNA such that an intron is retained or an exon skipped in the mature mRNA molecule. Silent mutations occur when there is no change in the amino acid sequence because although the DNA sequence changed, the amino acid coded for by the mRNA codon did not change because of redundancy in the genetic code. In addition to point mutations, which retain the same number of nucleotides, insertions or deletions of bases can also occur. Most commonly involving one or two bases, such insertions or deletions cause frameshift mutations and alter the reading frame of the codons in the mRNA. The amino acid sequence downstream from the insertion is typically altered substantially.

In addition to intragenic changes, polymorphisms can also occur in regulatory regions. These regulatory polymorphisms may alter the binding of transcription factors, enhancers, silencers, or similar molecules. The protein sequence remains intact, but protein expression can be substantially altered.

What Are the Classic Patterns of Genetic Inheritance? What Are the Recurrence Risk for Disorders Inherited in Each Fashion?

Classic Mendelian genetics is based on the principle that a specific disease or phenotype is determined by a single gene. Although the phenotype of an individual with a specific disorder is largely due to the specific mutati...