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Handbook of Clinical Adult Genetics and Genomics: A Practice-Based Approach
Handbook of Clinical Adult Genetics and Genomics: A Practice-Based Approach
Handbook of Clinical Adult Genetics and Genomics: A Practice-Based Approach
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Handbook of Clinical Adult Genetics and Genomics: A Practice-Based Approach

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Handbook of Clinical Adult Genetics and Genomics: A Practice-Based Approach provides a thorough overview of genetic disorders that are commonly encountered in adult populations and supports the full translation of adult genetic and genomic modalities into clinical practice. Expert chapter authors supplement foundational knowledge with case-based strategies for the evaluation and management of genetic disorders in each organ system and specialty area. Topics discussed include employing genetic testing technologies, reporting test results, genetic counseling for adult patients, medical genetics referrals, issues of complex inheritance, gene therapy, and diagnostic and treatment criteria for developmental, cardiovascular, gastrointestinal, neuropsychiatric, pulmonary issues, and much more.

  • Employs clinical case studies to demonstrate how to evaluate, diagnosis and treat adult patients with genetic disorders
  • Offers a practical framework for establishing an adult genetics clinic, addressing infrastructure, billing, counseling, and challenges unique to adult clinical genetics
  • Features chapter contributions from authors at leading adult genetics institutions in the US and abroad
LanguageEnglish
Release dateApr 10, 2020
ISBN9780128173459
Handbook of Clinical Adult Genetics and Genomics: A Practice-Based Approach

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    Handbook of Clinical Adult Genetics and Genomics - Shweta Dhar

    patients.

    Preface

    Shweta U. Dhar, Sandesh C.S. Nagamani and Tanya N. Eble

    Genetic testing is now increasingly being used for the diagnosis and management of numerous conditions. However, there are few, if any, concise yet comprehensive handbooks on genetic disorders that are commonly encountered in adults. Hence, we developed a convenient and easy-to-read resource for use in the clinics. The Handbook of Clinical Adult Genetics and Genomics is a compilation of genetic disorders encountered by healthcare practitioners. We envision that this book will help readers understand the clinical features of genetic disorders that present during adulthood and serve as a practical and useful guide for diagnosis and management. Whereas the field of adult genetics has undergone significant growth and expansion, there is still a dearth in literature regarding this subspecialty of clinical genetics. Likewise, there are few clinics that provide such subspecialty services. This book also offers a practical framework for setting up or expanding adult genetic services by addressing reimbursement, counseling, and use of other care-delivery models.

    The book is divided into four sections: Section I focuses on general concepts relevant to medical genetics; Section II is organized by organ systems and review disorders common to each system; Section III discusses the practical considerations for an adult genetic clinical practice including alternative delivery models such as telegenetics; and finally, in Section IV, we conclude with a view into the future with insights into precision medicine, pharmacogenomics, gene editing, and gene therapy.

    We express our deepest gratitude to all contributors who have so graciously found time to share their expertise. We are thankful to Elsevier for recognizing the need for and the potential of this book. In particular, we are grateful to Peter Linsley who conceived this project, Samantha Allard who guided us through the process and patiently answered our many questions, and our copy editors and project managers. We thank Chelsea Cook for her administrative assistance and for keeping us on track during this project. Our thanks also go out to our patients—they are the inspiration for all that we do. And of course, we would not have been able to do this without the unswerving support of our spouses (Utpal Dhar, Suman Rajagopalan, and Dan Eble) and children (Arman and Arjun, Suhas and Sanjay, and Elena and Annalise).

    Section I

    The Practice of Adult Genetics

    Outline

    1 Introduction to the practice of adult genetics

    2 Basic concepts of genetics and genomics

    3 Genetic evaluation of an adult

    4 Genetic counseling for adults

    5 Genetic testing in adults

    6 Transitioning to adult care

    7 Preconception and prenatal care

    1

    Introduction to the practice of adult genetics

    Shweta U. Dhar,    Department of Molecular & Human Genetics and Department of Internal Medicine, Baylor College of Medicine, Houston, TX, United States

    Abstract

    Many genetic disorders do not manifest until adulthood and multiple genetic factors may interact with multiple environmental factors over an individual’s lifespan to produce a clinical phenotype. Likewise, with earlier diagnosis and improvements in management, many individuals with congenital or childhood-onset conditions are now surviving into adulthood and seeking to transition their genetic care to an adult setting. Hence, the practice of adult genetics has emerged and continues to evolve.

    Keywords

    Adult genetics; genomics; medical students; genetics residents; combined internal medicine-genetics

    Overview of the field of adult genetics

    Clinical genetics has become a key discipline of modern day medicine since the completion of the human genome project. Genetic information is increasingly being used to inform medical care including diagnosis, treatment, and management of patients. A population study of genetic disorders [1] showed that 0.4% of the population have a single gene disorder (Mendelian disease), 0.2% have a chromosomal abnormality, 4.6% have a multifactorial condition, 0.1% have an obvious genetic abnormality of unknown inheritance, and 0.3% have congenital problems that are not genetic. While genetic disorders impact any organ system at any age in a given person’s life; historically, the practice of medical genetics has resided in the pediatric realm. With the current advances in technology and medicine, the genetic basis of many adult-onset diseases is being unraveled. We now know that many genetic disorders do not manifest until adulthood and multiple genetic factors may interact with multiple environmental factors over an individual’s lifespan to produce a clinical phenotype. Likewise, with earlier diagnosis and improvements in management, many individuals with congenital or childhood-onset conditions are now surviving into adulthood and seeking to transition their genetic care to an adult setting. Hence, the practice of adult genetics has emerged and continues to evolve [2,3]. The number of patients seen in different adult genetics practices has exponentially increased [2–4]. There are undoubtedly many more practices in the nation that are observing the same trends. While there are many centers with dedicated adult genetics clinics, there are others who see adult and pediatric patients in their combined genetic practices. Within these adult genetics practices, many centers have specialty clinics such as cancer genetics, cardiovascular genetics, connective tissue disorders, neurogenetics and inherited disorders of bone, to name a few.

    Why is it necessary to learn more about this?

    There are a variety of overarching reasons for referral to an adult genetics practice. These include diagnosis of a suspected genetic condition, risk assessment of asymptomatic individuals with a family history of a known genetic condition, management of childhood-onset conditions in adulthood, or preconception/carrier counseling for estimation of risks in pregnancy. A list of specific examples of indications for referral to adult genetics can be found in the publication by Eble et al. [3]. Genetics can play a role in different categories of disorders such as single gene/Mendelian disorders and multifactorial/complex disorders. More information about application of genetic information in complex disorders can be obtained from Chapters 28 and 29, while a detailed description of different disorders broken down by organ systems can be reviewed in Chapters 8 through 24 of this handbook. It is important to be aware of Mendelian disorders impacting every specialty in adult medicine so that appropriate diagnosis can be made and optimal and timely management is initiated. Table 1–1 lists different genetic disorders encountered by adult practitioners that are covered in this handbook. This is not a complete list but gives an idea of the diversity and variety of genetic disorders seen in adults and that every primary care practitioner as well as specialist may benefit by being aware of these conditions.

    Table 1–1

    It is important to remember that unlike children with genetic disorders, in the diagnosis of a genetic disorder in adults, one needs to sift through common age-related comorbidities that may confound the clinical picture. Patients have often visited with multiple specialties prior to their genetic evaluation and are left with frustration at their diagnostic odyssey. One needs to be sensitive about the challenges these individuals bring to their care. However, it is also essential to not attribute every symptom/sign to the underlying genetic disorder. Adults with genetic conditions can also develop common morbidities just as anyone else, which may merit their own evaluation and workup.

    How are we teaching our medical students?

    Medical school lays the grass roots of medical education and practice for our students. If the students are taught clinical genetics within the framework of pediatrics, they will not be able to appreciate the importance of recognizing genetic disorders if they intend to practice adult medicine. Hence, it is imperative that medical school curriculum be balanced between pediatric and adult genetics. Students should be aware of the utility of genetics in adults and be able to recognize genetic conditions in different specialties. Many curricular reforms are underway and national societies such as the Association of Professors of Human and Medical Genetics and the American College of Medical Genetics and Genomics are working hard to ensure that students get a well-rounded education in genetics. Some schools such as Baylor College of Medicine have implemented specialized tracks [5] called the Genetics and Genomics Pathway that provide enrichment in genetic education beyond the core curriculum in genetics.

    How are we training our genetics residents?

    Genetics residency programs are located in different departments across the country based on the strength of the program and its structure within the academic center. There is a disparity in clinical training of future geneticists based on whether their training program is more focused on pediatric or adult training. Given the paucity of adult trained geneticists, the number of adult genetics focused clinical programs is small. Hence, trainees may be getting a more biased approach to medical genetics that is heavily influenced by pediatric presentations. Establishment of a genetics curriculum in internal medicine residencies [6] as well as combined internal medicine-genetics residency programs [7] may help mitigate some of these limitations and make trainees aware of the expanding world of adult genetic medicine.

    Who will impart genetic care to adult patients?

    Pediatricians are aware of genetic disorders that are seen in children and can manage them or refer them to genetic specialists. In contrast, the care of the adult patient with a genetic disorder is fragmented among different specialties and adult trained providers may or may not be comfortable managing these conditions. In addition, it is harder to find geneticists that are trained in adult medicine. Hence, it becomes important to train all providers, regardless of specialty, about the impact of genetics in medical care. A cardiologist may need to recognize that a spontaneous aneurysm in a 42-year-old individual with no past medical problems may have resulted from a connective tissue disorder, or a gastroenterologist who sees multiple polyps in a 50-year-old at his first colonoscopy must think that his patient may indeed have a familial polyposis syndrome.

    Why do we need a book like this?

    The primary objective of this book is to provide a clinical overview of genetic disorders that are commonly encountered in the adult population within different specialties of medicine. A practical approach for diagnosis and management within each organ system will be detailed, thus educating the reader about the clinical aspects of adult genetics. This book will also serve as a basis for learning the challenges and uniqueness about adult genetic practices. Residents and practicing physicians of all subspecialties will find this book to be a handy resource to learn about genetics relevant to their fields of practice. The currently available genetics textbooks are typically large reference books that are most likely relevant only to geneticists and not clinicians of other specialties. This book will serve as a practical handbook that trainees of multiple subspecialties including genetics can carry during rounds. In addition, there are no books on the practical approach to the care of an adult with a genetic disorder. This book will use case-based scenarios to help understand diagnostic evaluation and management of patients.

    The book is divided into four sections. Section I outlines the basic concepts of genetics and genomics including genetic testing methodologies and genetic counseling. Section II is a review of the different genetic disorders relevant to each of the organ systems, and the reader can use the case vignettes to understand clinical scenarios they may experience in practice. Section III focuses on access to genetic services and here the reader can understand the concepts of billing and reimbursement as well as alternative models for delivery of genetic and genomic care. A chapter on the ethical, legal, and social implications of genetic medicine is also presented. Finally, Section IV directs the reader to the future with discussions on precision medicine, pharmacogenomics, and gene therapy.

    Points to remember

    • Adult genetics is an evolving subspecialty of clinical genetics.

    • Genetics will impact medical care at all ages and in all subspecialties.

    • Every physician needs to be aware of genetic disorders that impact adults so that appropriate diagnosis and timely management can be initiated.

    References

    1. Baird PA, Anderson TW, Newcombe HB, Lowry RB. Genetic disorders in children and young adults: a population study. Am J Hum Gen. 1988;42(5):677–693.

    2. Taylor MR, Edwards JG, Ku L. Lost in transition: challenges in the expanding field of adult genetics. Am J Med Genet C Semin Med Genet. 2006;142C(4):294–303.

    3. Eble TN, Nagamani SC, Franco LM, Plon SE, Blazo M, Dhar SU. The practice of adult genetics: a 7-year experience from a single center. Am J Med Genet A. 2013;161A(1):89–93 https://doi.org/10.1002/ajmg.a.35684 Epub 2012 Dec 13.

    4. Gay EA, Byers PH, Bennett RL, Bird TD, Hisama FM. Trends over 42 years in the Adult Medical Genetics Clinic at the University of Washington. Genet Med. 2019;21(6):1457–1461 https://doi.org/10.1038/s41436-018-0329-5 Epub 2018 Oct 16.

    5. Dhar SU, Alford RL, Nelson EA, Potocki L. Enhancing exposure to genetics and genomics through an innovative medical school curriculum. Genet Med. 2012;14(1):163–167 https://doi.org/10.1038/gim.0b013e31822dd7d4 Epub 2011 Sep 26.

    6. Riegert-Johnson DL, Korf BR, Alford RL, et al. Outline of a medical genetics curriculum for internal medicine residency training programs. Genet Med. 2004;6(6):543–547.

    7. https://www.abim.org/certification/policies/combined-training/internal-medicine-medical-genetics-and-genomics/overview.aspx.

    2

    Basic concepts of genetics and genomics

    Jennifer E. Posey,    Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, United States

    Abstract

    An understanding of the relationship between genes or genetic variants and their associated phenotypes forms one cornerstone upon which the practice of genetics has been built, supporting the identification of molecular diagnoses that inform disease management as well as recurrence risks for families. The sections below provide a framework for understanding genomic architecture and DNA structure, genetic and genomic variation, and modes of disease trait inheritance in the context of genetic disease in adults.

    Keywords

    Genomic architecture; DNA structure; gene structure; chromosomes; variant pathogenicity; modes of inheritance

    Introduction

    The last several decades have seen unprecedented growth in our understanding of the genetic and genomic basis of human disease. In many ways, this growth has been driven by a unique combination of clinical insight and technology development, enabling precise detection of rare genetic and genomic variants to be linked directly to clinically observed phenotypes. Completion of the international Human Genome Project in 2003 provided the first draft reference sequence of the human genome, a haploid sequence of ~3 × 10⁹ base pairs (bp) which led to elucidation of the locations and architectures of ~20,000 protein-coding genes. The continued development of next-generation sequencing technologies has given clinicians and researchers a means to probe the genome broadly without sacrificing precision.

    Unraveling the associations between an individual’s genes, genetic variants (their genotype), and their clinical presentation (their phenotype) will begin—and in some instances has already begun—to form the cornerstone of precision therapeutics. Discoveries involving these genotype–phenotype relationships are cataloged in the Online Mendelian Inheritance in Man (OMIM) database, with more than 4000 protein-coding genes (roughly 20% of the estimated 20,000 protein-coding human genes) associated with one or more disease phenotypes (www.OMIM.org, May 30, 2019) [1]. These data illustrate the breadth of discovery to date, as well as the tremendous amount of discovery that remains.

    Functional elements of the human genome

    To understand how genetic and genomic variations can contribute to genetic conditions in adults, it is helpful to first review the structure of deoxyribonucleic acid (DNA) in the context of the genomic architecture.

    Molecular architecture of DNA

    The structure of DNA itself is elegant in its relative simplicity as a polymer consisting of only four nucleotides. The precise sequence of the nucleotides is responsible for encoding the instructions needed for an organism to develop and reproduce. Each nucleotide is composed of a purine [adenine (A) or guanine (G)] or pyrimidine [thymine (T) or cytosine (C)] base, as well as one phosphate molecule and one sugar moiety. The molecular architecture of DNA imposes a directionality on each polymer, or strand. A DNA strand sequence is classically represented in a 5′-to-3′ direction. In the cell, DNA exists as a double-stranded helix, with the sequence of one strand representing the inverse complement of the sequence of the opposite strand (Fig. 2.1). The strands are held together by hydrogen bonds that form between purine-pyrimidine base pairs: A-T and G-C. This structure enables stable transmission of genetic information from one generation to the next.

    Figure 2.1 Gene structure, and the DNA, RNA, and protein molecules involved in transcription and translation.

    Each gene has a transcription initiation and transcription termination site, which mark the beginning and end of the encoded mRNA. mRNA is single-stranded, and the thymine (T) of DNA is replaced by uracil (U). mRNA codons (groups of three nucleotides) encode the amino acids of a protein.

    Nuclear and mitochondrial genomes

    If stretched end-to-end, a single cell’s nuclear genome would span approximately 2 meters in length. Levels of packaging of the nuclear DNA form chromosomes, imposing a higher-order structure on the nuclear genome and facilitating both cell division and gene expression. Each cell consists of 46 chromosomes: two copies of each autosome (chromosomes 1–22), and two sex chromosomes (either two X chromosomes, or one X and one Y). These chromosomes consist of the DNA as well as a protein family called histones which form 8-protein complexes called octamers around which the DNA double helix is wound. Octamers are spaced about 20–60 bp from each other, and each has nearly two full turns of DNA (~140 bp), giving a beads on a string appearance to the DNA-histone complex called the nucleosome. Nucleosomes are further organized into cylindrical structures called solenoids, which are bundled into DNA domains measuring approximately 100,000 bp, organized by a nuclear protein scaffold to form chromatin. During cell division, this structure will condense to display the chromosome structure with which readers are most familiar: the 46 paired chromosomes that can be observed by karyotype analysis, each consisting of one short (p) arm and one long (q) arm joined by a centromere.

    In addition to the nuclear genome, every cell contains hundreds, if not thousands, of mitochondria, each harboring multiple copies of the mitochondrial genome. The mitochondrial genome is much smaller than the nuclear genome, consisting of only 37 genes encoded on a single, circular chromosome of 16,569 bp. Proper mitochondrial functioning depends on these 37 genes which encode mitochondrial transfer RNA and components required for oxidative phosphorylation. Many nuclear-encoded genes are also essential for mitochondrial function, and this is one reason why mitochondrial conditions can display very different patterns of inheritance in families.

    Gene structure

    Each of the approximately 20,000 genes in the human genome has several components. These include both the nucleotide sequence that encodes the amino acid sequence of the protein itself, as well as several regulatory elements that are important for gene expression, including the transcription of DNA into RNA, and the translation of that RNA into an amino acid sequence to form a protein (Fig. 2.1). Transcription describes the process whereby the DNA sequence is copied into a messenger RNA (mRNA) sequence. Subsequently, translation is the process by which this mRNA sequence is used to generate an amino acid sequence encoding the intended protein. It is to be noted that only 1%–3% of the genome contains protein-coding genes.

    The gene promoter sequence regulates the beginning of RNA transcription at the transcription start site, which is typically the beginning of the first exon. The exons themselves encode the intended amino acid sequence. The exons may be separated by one or more intronic sequences that may contain enhancers or other regulatory elements. These introns are spliced out of the final mRNA product. The 5′ portion of the first exon, and the 3′ portion of the final exon also contain untranslated regions (UTRs, one 5′UTR and one 3′UTR) that are transcribed into the mRNA sequence and contain important elements for RNA function and stability, but do not contribute to the final amino acid sequence of the encoded protein.

    In the mRNA sequence, an initiator codon marks the site at which protein translation will begin and always encodes the amino acid methionine (M, Met); this methionine will become the N-terminus, or amino-terminus of the polypeptide chain, so named for the amino group that is exposed at this end of the protein. From this point, the mRNA sequence consists of a series of consecutive codons, each comprising three bases, which specify the order of particular amino acids within the protein being made. As subsequent sections will discuss, the reading frame established by this triplet code, which defines the position of each codon, is important for accurate protein translation. Translation stops when one of the three stop codons is encountered. The final amino acid becomes the C-terminus or carboxy-terminus of the protein named for the carboxyl group that is exposed at this end of the polypeptide chain.

    Human genomic variation

    An essential foundation for the implementation of individualized, precision medicine is understanding relationships among genes and modes of disease inheritance. Enabled with these data, a clinician can provide individuals and families with key information regarding molecular diagnoses, their implications for current and future health, and recurrence risks for a given family. Although the following sections will detail distinct classifications of variant types and modes of disease inheritance, it is important to consider that for a given gene different variant types and different modes of inheritance may be observed in association with distinct disorders. LMNA is one such example, for which rare variants can lead to autosomal dominant (AD) conditions such as dilated cardiomyopathy, Hutchinson–Gilford progeria syndrome, and Emery–Dreifuss muscular dystrophy, or autosomal recessive (AR) conditions such as Charcot-Marie-Tooth disease or, in rare instances, Emery–Dreifuss muscular dystrophy. To date, over 30% of disease genes have been definitively associated with more than one rare disorder (www.OMIM.org).

    Types of genetic and genomic variants

    Genetic and genomic variants can range in size from a single-nucleotide substitution [a single-nucleotide variant (SNV)] to a small insertion/deletion (indel) of 1–50 bp, to a much larger structural variant (SV) that can impact one or more genes.

    Single-nucleotide variant

    SNVs that occur within the protein-coding portion of a gene can result in an amino acid residue change in the encoded protein, in which case they are termed nonsynonymous or missense variants. A change resulting in a stop codon being coded is called a nonsense or stop-gain variant and will prematurely truncate the protein. Alternatively, because of the redundancy of the genetic code, with some amino acid residues encoded by more than one codon, some SNVs will result in no amino acid residue change; these are termed synonymous variants. Splice site SNVs located near intron/exon boundaries can impact splicing mechanisms, leading to loss of one or more exons, or inclusion of intronic sequence within the final mRNA transcript.

    Indel variants

    Indel variants will shift the codon reading frame: if the frame is shifted by one or two nucleotides, the codons subsequent to the variant will be out of frame, and the variant will be termed a frameshift variant (the new frame will encode a new amino acid sequence that ends once a stop codon is encountered within the new frame). In contrast, indel variants that maintain the codon frame (e.g., insertion of three nucleotides, or deletion of six nucleotides) will produce a non-frameshift variant.

    Large SVs

    Large SVs are called so because they impact genomic structure. Depending on their size, they may impact a part of a gene, such as a single or few exons, or a large number of genes. Copy neutral SVs, such as inversions, impact the structure of the genome without impacting the copy number of each gene. These may be pathogenic if they disrupt the gene: either the gene sequence or its regulatory elements. Copy number variants (CNVs) alter the number of copies of a particular genomic segment. Copy number losses are deletions in which one (if heterozygous) or both (if homozygous) copies of a DNA segment are lost. Copy number gains are duplications in which one or more additional copies of a DNA segment are present. These CNVs can cause disease through impacts on gene dosage and can also result in gene interruption depending on the precise location of their breakpoints.

    Chromosomal variation

    While often thought to present clinically during childhood, chromosomal aneuploidies and translocations are relevant to the practice of adult genetics. Chromosomal aneuploidies describe the occurrence of an abnormal number of chromosomes within a cell—technically, this can refer to either one or more absent chromosomes (e.g., Turner syndrome, in which there is only one sex chromosome: 45,X) or one or more extra chromosomes (e.g., trisomy 21, in which there is an extra chromosome 21: 47,XX,+21). The majority of chromosomal aneuploidies are not viable, but individuals with Turner syndrome and trisomy 21 regularly survive into adulthood.

    Chromosomal translocations occur when there is a rearrangement of DNA segments between two chromosomes. These may be balanced if copy number is maintained, or unbalanced if copy number gains and/or losses occur due to the rearrangement. Robertsonian translocation is one type of translocation that involves the joining of the q arms of two acrocentric chromosomes (chromosomes 13, 14, 15, 21, 22). Because the acrocentric chromosomes do not contain protein-coding genes on their p arms, loss of the p arms in the course of these translocations is not considered an unbalanced event; however, the translocation itself can lead to errors in chromosomal segregation during meiosis and gamete formation, thus increasing the risk of an unbalanced translocation in the next generation.

    Uniparental disomy is one additional form of genomic variation that can impact disease expression. The expression of a subset of genes in the human genome is tightly regulated from either the maternally or paternally inherited chromosome, such that biparental chromosome inheritance is essential for normal development. Although a majority of individuals will inherit one set of chromosomes from each parent, and thus have one maternal and one paternal copy of every chromosome, uniparental disomy can occur, in which both copies of a particular chromosome are inherited from the same parent. Depending on the chromosome impacted, consequent errors in gene regulation can impact the development and expression of disease.

    Impact of genetic and genomic variation

    As one may expect, different variant types can have different impacts on protein function. Scientifically these are classically conceptualized in one of the following five categories: loss-of-function (LoF [amorph]), partial LoF (hypomorph), dominant-negative (antimorph), increase in function (hypermorph), and novel function (neomorph). From a clinical perspective, the classification of variants focuses on whether the impact of the variant can result in expression of the disease: those variants known to be disease-causing are classified as pathogenic, and those variants known not to result in disease expression are classified as benign. A five-tiered system has been proposed by the American College of Medical Genetics and Genomics (ACMG) to provide a framework for classification of variants: these five tiers are pathogenic, likely pathogenic, variant of unknown significance or VUS, likely benign, and "benign [2]."

    Modes of inheritance

    It is important to remember that modes of inheritance refer not to the segregation of a particular variant, but to the segregation of a disease trait or phenotype observed within a family’s genetic pedigree. The following sections will first describe the more classic and straightforward forms of Mendelian inheritance, followed by several examples of more complex inheritance patterns.

    Autosomal Dominant (AD)

    AD inheritance is defined by the observation of a disease trait in which male and female offspring of an affected individual each have a 50% chance of being affected. Typical genetic pedigrees will demonstrate transmission of the trait from one generation to the next, and the underlying genetic variant will be present in only one of the two copies (heterozygous or monoallelic; i.e., one of the two alleles or copies) of the relevant gene. The term autosomal refers to the observation that AD conditions arise from a variant on an autosome, defined as any chromosome (Chr 1–22) other than the sex chromosomes (Chr X and Y). Some individuals with an AD condition may have a variant that arose "de novo," meaning that a new mutation occurred around the time of conception and thus is not present in either parent.

    Autosomal Recessive (AR)

    AR inheritance is defined by the observation of a disease trait that requires the underlying genetic variant(s) to impact both copies (biallelic or both alleles) of the relevant gene. Individuals who have an AR disease trait may have either the same variant present on both alleles of the gene (homozygous) or two variants, each affecting one copy ("in trans) of the gene (compound heterozygous). Parents of individuals who have an AR condition are considered unaffected carriers" of the condition and are expected to be heterozygous for an etiologic variant. Children born to such a carrier couple will have a one in four chance of inheriting both pathogenic variants (and thus having the AR condition), a two in four chance of inheriting only one of the pathogenic variants (and thus being an unaffected carrier), and a one in four chance of inheriting neither variant.

    X-linked (XL)

    XL inheritance is defined by the observation of a disease trait that segregates with a gene on the X chromosome. Males and females are usually—but not always—differentially affected by the variants that cause these conditions, as women have two copies of the X chromosome and men have only one copy of the X chromosome (and thus are hemizygous). Classically, XL conditions were considered to be either dominant or recessive depending on whether heterozygosity in a female was sufficient for disease expression. Some XL conditions indeed affect primarily males and are inherited from unaffected mothers. In contrast, other XL conditions impact males and females similarly, whereas others are observed only in females because the condition in males results in early/embryonic lethality. Sex-limited traits, which are distinct from XL conditions, are typically associated with variants in the autosomes but are only clinically observed in one of the two sexes.

    Mitochondrial

    Mitochondrial inheritance is defined by the observation of a disease trait that segregates with the mitochondrial genome. As mitochondrial genomes are inherited exclusively from the maternal germline, disease traits that result from a variant in the mitochondrial genome are inherited solely from the mother. It is important to note that not all mitochondrial diseases display mitochondrial inheritance. As some genes essential for mitochondrial function are encoded on the nuclear autosomes, and some are encoded within the mitochondrial genome, the class of conditions resulting from mitochondrial dysfunction can display either AR or mitochondrial inheritance. Note that despite this dichotomy, mitochondrial disease associated with a particular gene will display either autosomal or mitochondrial inheritance, determined by the location of that particular gene within the genome. Because more than two copies of the mitochondrial genome are present in each cell, variants are not described as heterozygous or homozygous, but as homoplasmic (present in all copies of the mitochondrial genome) or as heteroplasmic (present in a subset of copies of the mitochondrial genome, Fig. 2.2). The degree of heteroplasmy (the percentage of mitochondrial genomes that have the variant) can vary from one tissue to the next and can impact the expression and severity of disease.

    Figure 2.2 Mitochondrial heteroplasmy and homoplasmy.

    Cells will contain one diploid (two copies) set of the nuclear genome, which is present in the nucleus of the cell. However, numerous mitochondria and mitochondrial genomes exist within the cell. For simplicity, the mitochondria have not been shown. Each mitochondrial genome is represented by a small oval: white ovals indicate genomes that do not have a mitochondrial variant, and shaded ovals indicate genomes that do contain a mitochondrial variant. Heteroplasmy and homoplasmy are used to describe the percentage of mitochondrial genomes that have a given variant.

    Imprinting

    Rare conditions resulting from imprinting errors (such as Angelman syndrome and Prader-Willi syndrome) can be present when genes that are typically critically expressed from either the maternally or paternally inherited allele of a genomic region are inactive. These conditions will display very distinctive inheritance patterns in families, as expression of disease is determined by whether the variant allele is inherited from the mother or father. For example, individuals with Prader-Willi syndrome are most often missing a segment of the paternal copy of chromosome 15. However, if the same segment of chromosome 15 is absent only on the maternal copy of chromosome 15, the individual in question will not have Prader-Willi syndrome, but will instead develop a distinct condition called Angelman syndrome. Individuals with either condition may simply have a copy number loss (a deletion), or may have uniparental disomy resulting in a neutral copy number of this region of chromosome 15, or a defect in the imprinting machinery itself.

    Digenic

    Digenic inheritance refers to conditions that require rare pathogenic variants at two distinct loci or genes in order for the disease to be manifest (Fig. 2.3). The loci themselves are observed to segregate independently within a family (they are typically on distinct chromosomes), and the individuals who inherit pathogenic variants at both loci will develop the disease trait. Particular subtypes of Bardet-Biedl syndrome and Usher syndrome are examples of conditions that exhibit digenic inheritance.

    Figure 2.3 Complex modes of inheritance.

    Digenic inheritance involves variants at two loci that are both required for expression of the disease trait. Dual molecular diagnoses involve variants at two loci that each is associated with a disease trait—both disease traits can segregate independently within a family. Shown here is a proband with one recessive condition resulting from biallelic variants, and one dominant condition resulting from a de novo variant not present in either parent. Mutational burden describes the phenomenon in which the severity, expression, or age of onset of a trait may be modified by variants at additional loci. Shown here are fully penetrant biallelic variants conferring a recessive condition, as well as two additional non-penetrant variants (which by themselves do not cause disease) that modify the phenotype. Incomplete penetrance can be observed when disease trait manifestation requires one rare LoF allele in combination with a second, often more common, hypomorphic allele, for a disease trait to be manifest. Squares (male) and circles (female) demonstrate the parent-child pedigree structure. Circles filled by light gray background are affected offspring. Two chromosomes are represented with rare, pathogenic variants indicated by red ovals, and hypomorphic variants that do not independently confer a disease trait are indicated by gray ovals.

    Complex inheritance

    Many commonly occurring multifactorial disorders such as diabetes, hypertension, and coronary artery disease run in families. The genetic risk in these disorders is typically due to multiple genetic and genomic variants, each with a small effect size. While these conditions tend to cluster in families, the expression of disease is dependent on the interaction between genetic and environmental factors.

    Special considerations

    Dual molecular diagnoses

    Dual molecular diagnoses refer to a scenario in which an individual is found to have not one, but two molecular diagnoses, resulting in two disease traits which are observed clinically as a blended phenotype (Fig. 2.3). When the disease pairs are phenotypically similar, they can be categorized as overlapping phenotypes and may appear clinically to be a single condition; in contrast, when the disease pairs are phenotypically different, they can be categorized as distinct phenotypes and may appear clinically as an apparently novel condition. In either case, each disease trait will be observed to segregate independently of the other within the family. Dual molecular diagnoses, and multiple molecular diagnoses involving two, three, or even more loci, were once thought to be a relatively rare occurrence. However, they are now well-established to occur in at least 5% of individuals for whom genome-wide clinical testing is diagnostic [3].

    Mutational burden

    Mutational burden refers to the observation that a given phenotype resulting from a highly penetrant pathogenic variant can be modified (in severity, character, timing of onset) by additional variants that impact other genes acting within the same pathway or functional unit (Fig. 2.3). These additional variants may not be penetrant by themselves, nor segregate perfectly with disease in a family, but can explain the observation of intrafamilial phenotypic variability observed in some conditions; those individuals with more severe phenotypes can be found to have a higher mutational burden, in addition to the primary, etiologic pathogenic variant. Similar modifier effects may result not from genetic or genomic variants, but rather from epigenetic modifiers and/or environmental exposures.

    Incomplete penetrance

    Incomplete penetrance of a condition refers to the observation that not all individuals who have an etiologic variant for a particular disease trait will actually develop that disease trait (Fig. 2.3). This phenomenon may explain the apparent skipping of generations in an AD pedigree.

    Relevance to clinical care

    Basic concepts of genetic and genomic variation and inheritance establishes a framework for understanding the clinical impact of a particular variant or set of variants on disease manifestation. This genotype–phenotype relationship can inform molecular diagnoses for individuals and guide medical treatment and expectant management, while often providing the why that patients so often seek. This enables a precision molecular diagnosis, guiding clinical management of disease for the individual and their family [4].

    Points to remember

    • Protein-coding genes comprise less than 3% of the genome.

    • Genetic and genomic variation can be categorized as SNVs, indels, CNVs, and copy neutral variants.

    • Understanding the pattern of inheritance is critical in identifying a genetic disorder and assessing risk for family members.

    References

    1. Amberger JS, Bocchini CA, Scott AF, Hamosh A. OMIM.org: leveraging knowledge across phenotype-gene relationships. Nucleic Acids Res. 2019;47(D1):D1038–D1043.

    2. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424.

    3. Posey JE, Rosenfeld JA, James RA, Bainbridge M, Niu Z, Wang X, Dhar S et al. Molecular diagnostic experience of whole-exome sequencing in adult patients. Genet Med 2016;18(7):678–685.

    4. Posey JE, O'Donnell-Luria AH, Chong JX, et al. Insights into genetics, human biology and disease gleaned from family based genomic studies. Genet Med. 2019;21(4):798–812.

    3

    Genetic evaluation of an adult

    Aeron M. Small¹, Monica Giovanni² and Michael F. Murray³,    ¹Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States,    ²Center for Genomic Health, Yale New Haven Hospital, New Haven, CT, United States,    ³Genetics, Yale School of Medicine, New Haven, CT, United States

    Abstract

    Most adult care providers have limited experience in incorporating DNA-based testing into the clinical care of their patients. This chapter reviews a basic approach to the evaluation of an adult who presents with concern for a genetic disorder. An overview of common presentations, importance of family history, available genetic testing, and the approach to management is discussed here.

    Keywords

    Phenome; genome; family history; genetic evaluation; genetic testing; monogenic disease; polygenic disease

    Introduction

    Most adult care providers have limited experience in incorporating DNA-based testing into the clinical care of their patients. Twenty-first century standards of care will increasingly use DNA-based testing to inform disease risk identification, disease diagnosis, and long-term management. The incorporation of DNA-based testing into adult care includes three categories of genetic or genomic disorders: classical genetic disorders (e.g., rare monogenic or chromosomal syndromes), monogenic instances of common disease (e.g., familial hypercholesterolemia and BRCA1/2-associated cancer), and polygenic risk for common diseases.

    The approach to diagnosis and management of genetic disorders in adult patients requires careful consideration of clinical features (including a history of presenting symptoms, a careful physical examination, and review of available laboratory and imaging data), family history, cost and efficacy of genetic diagnostic testing, and attention to the implications of testing for the management of a patient’s disease. Here, we review a basic approach to the evaluation of an adult who presents with concern for a genetic disorder. In this chapter, we provide an overview of common presentations and discuss the importance of family context, available diagnostic DNA technologies, genetic and genomic contributions to disease, and approaches for follow-up and

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