Human Genetics Pt 2 PDF

Genetics 2: Modes of Inheritance Genetic Couseling Lewis J Waber, MD PhD Adjunct Professor, Arcadia University  In accordance with the guidelines set forth in the syllabus, it is expected the student will: 1) Explain the principles of inheritanc...

Genetics 2: Modes of Inheritance Genetic Couseling Lewis J Waber, MD PhD Adjunct Professor, Arcadia University  In accordance with the guidelines set forth in the syllabus, it is expected the student will: 1) Explain the principles of inheritance including segregation, independent assortment, autosomal dominant, autosomal recessive, and sex-linked inheritance 2) Identify components in the family history to identify the pattern Lecture 3) of inheritance Identify “genetic red flags” in a personal and family medical Objectives: history 4) Be able to interpret a pedigree Modes of 5) Be able to obtain an accurate pedigree Inheritance 6) Define reduced penetrance, variable expressivity, incomplete dominance and codominance 7) Define allelic heterogeneity, pleiotropy, and genetic heterogeneity 8) Define mosaicism, homozygosity, heterozygosity, and hemizygosity 9) Define lyonization, Barr body, XIST, and imprinting  In accordance with the guidelines set forth in the syllabus, it is expected the student will: 1) Differentiate between screening, diagnostic, and predictive testing Lecture 2) Identify patients who would benefit from referral to a genetic counselor Objectives: 3) Counsel a patient on genetic screening and Genetic diagnostic testing options 4) Describe the difference in information obtained Counseling from a chromosome test versus a comparative genomic hybridization 5) Explain the term ‘variant of uncertain significance’ 6) Discuss psychosocial aspects of genetic counseling including ethics, privacy, financing, and follow-up Modes of Inheritance Genetics 2: Part 1 ©2009, Creative Commons License, Wikimedia Commons, File:4 Kittens.jpg  1) Explain the principles of inheritance including segregation, independent assortment, autosomal dominant, autosomal recessive, and sex-linked inheritance Lecture 2) Identify components in the family history to identify the pattern of inheritance 3) Identify “genetic red flags” in a personal and family medical history Objectives: 4) Be able to interpret a pedigree Modes of 5) Be able to obtain an accurate pedigree 6) Define reduced penetrance, variable expressivity, incomplete dominance and Inheritance codominance 7) Define allelic heterogeneity, pleiotropy, and genetic heterogeneity 8) Define mosaicism, homozygosity, heterozygosity, and hemizygosity 9) Define lyonization, Barr body, XIST, and imprinting Explain the principles of inheritance including segregation, independent assortment, autosomal dominant, autosomal recessive, and sex-linked inheritance.  Mendel's laws of inheritance are three fundamental principles that describe the way in which traits are passed from parents to offspring. These laws were developed by Gregor Mendel, a monk and botanist in the present day Czech republic who conducted extensive experiments on pea plants in the mid-19th century.  The three laws of inheritance proposed by Mendel are: 1. Law of Segregation 2. Law of Independent Assortment 3. Law of Dominance  These laws form the basis of modern genetics and have been confirmed by numerous subsequent experiments. They provide a simple and elegant explanation for the inheritance of traits and continue to be an important part of genetics research and education today. Source: ChatGPT  1. Law of Segregation a 1. During gamete formation, the two alleles of a gene segregate from each other such that each gamete carries a a a only one allele of each gene. This a means that when two alleles for a trait A A A are present in an individual, they aa separate during the formation of A gametes (sperm or egg cells) and only A A one allele is passed on to each offspring. A ©2016, WikiMedia Commons, Creative Commons License, File:Meiosis Overview new.svg  2. Law of Independent Assortment The inheritance of one trait is independent of the inheritance of other traits. This means that the alleles of different genes assort independently during gamete formation, resulting in the inheritance of traits that are a combination of the parental traits. © Jan 9, 2023 OpenStax. Creative Commons License. Access for free at https://openstax.org/books/concepts-biology/pages/1-introduction  3. Law of Dominance  In a cross between two homozygous parents that differ in one trait (for example, one parent has a dominant allele and the other has a recessive allele), the offspring will inherit the dominant allele and exhibit the dominant trait. The recessive allele will only be expressed if both copies of the gene are recessive. Tabitha: A Tabby Cat  Striping pattern controlled by Tabby locus: TaM produces mackerel pattern Tab produces classic (blotched) pattern x Law of Dominance: TaM/TaM Tab/Tab Tabby Cats Mackerel allele is TaM/Tab TaM/Tab TaM/Tab TaM/Tab dominant Classic (blotched) allele is recessive Single gene disorders or traits  Simple inheritance patterns (Mendelian)  Dominant  Recessive  X-linked  Due to variations at one genetic locus  Genes with major effects  > 5,000 described   Most inborn errors of metabolism  PKU, urea cycle, organic acid, etc  Cystic fibrosis  Most are autosomal recessive  Most chondrodysplasias Single Gene  Achondroplasia, Stickler syndrome, SED  Apert, Pfeiffer, Crouzon (craniosynostosis) Disorders  Most are autosomal dominant  Some syndromes  Marfan  Neurofibromatosis  Tuberous sclerosis  Fragile-X Dominant inheritance  Only one gene variant needed to cause problems  Heterozygotes manifest the trait  Passed from parent to child  Family history of condition in other relatives  Can be caused by new mutation (parent unaffected)  Effects often variable within families  Recurrence risk to children of affected person is 50%  Recurrence risk to unaffected parents of affected child (i.e. new mutation) is 1500 known pathologic variants Genetic  Cystic fibrosis is associated with Heterogeneity  Pancreatic insufficiency  Chronic pulmonary disease and Pleiotropy:  Diabetes Genotype-  Infertility in males Phenotype  Some CFTR variants are more likely to cause pancreatic Correlation insufficiency than other variants.  Some CFTR variants cause male infertility (congenital absence of the vas deferens) without other symptoms.  Some CFTR variants are associated with milder or later onset lung disease Genetic Heterogeneity: Cat coat colors Several genetic loci and alleles at those loci interact to produce the different color patterns seen in cat coats. Define mosaicism, homozygosity, heterozygosity, and hemizygosity Mosaicism:  Variation in genotype in different cells of the body  Caused by post-fertilization events  Mutation (single gene variants)  Non-disjunction (chromosomal variants) Homozygosity:  Both alleles at a locus have a pathologic or other variant Heterozygosity:  One allele at a locus is normal (wild type), the other is a pathologic variant Hemizygosity:  Males with variants at a locus on their X-chromosome  X-chromosome inactivation (XCI) is a process in female mammals that balances gene expression levels between males and females. Define Because females have two X chromosomes, compared to males who only have one, it is necessary to silence one of the X lyonization, chromosomes in each female cell. This process ensures that both Barr body, males and females express the same number of genes from the X chromosome. Source: ChatGPT XIST, and The inactive X-chromosome can be visualized at the edge of the nucleus as a Barr Body. imprinting The random inactivation of X-chromosomes in females is termed “Lyonization”.  In 1949 Barr and Bertram published finding the presence of a condensed piece of chromatin at the edge of nuclei in XX individuals (female cats), but not XY individuals (male cats). This condensed chromatin is called the Barr Body. The number of Barr bodies in a cell is one less than the number of X- chromosomes in the cell nucleus. Figure after M. Barr (1963) by SM Carr Barr Body Geneticists thought that the sex of an individual was determined by the number of X-chromosomes, which would require that both X- chromosomes be expressed. In 1959, researchers discovered the male sex-determining gene (SRY) was on the Y chromosome, and that the presence or absence of a Y- chromosome determined male or female sex respectively.   In 1960 Mary Lyon demonstrated that only one of the X-chromosomes in females (mice) is active.  The other X-chromosome is permanently inactivated.  It appears as the Barr body in the nucleus  The inactivation occurs early in embryologic development and Lyonization is maintained in subsequent cell divisions  Females are mosaics with some cells expressing genes on one X, and other cells expressing the genes on the other X.  This mechanism (called Lyonization) compensates for the difference in gene dosage between XX and XY individuals.  Female cats that are heterozygous at the orange (X-linked O) locus have patches of fur Lyonization: expressing the Orange gene and other patches Tortoiseshell expressing their tabby and color patterns. Calico cats © 2022 Dr. David W. Silversides, LabGenVet.ca 2006, Public Domain, WikiMedia Commons, File:Tortoiseshell © 2020, Creative Commons License, cat Cindy in a box.jpg WikiMedia Commons, File:Found A Pretty Calico Kitty.jpg  The gene responsible for X-chromosome inactivation is called Xist, which stands for X-inactive specific transcript. Xist is a non-coding RNA gene, meaning that it does not produce a protein product. Instead, it produces an RNA molecule that coats the inactive X chromosome, causing it to become silenced. During XCI, Xist RNA is produced from one of the two X chromosomes in each female cell. The Xist RNA molecule then spreads along the entire length of the chromosome, recruiting proteins that modify the chromosome structure and silence gene expression. As a result, only Mechanism of one of the two X chromosomes in each female cell is active, and the other is silenced and compacted into a dense structure called a Barr X-inactivation: body. Source: ChatGPT Xist Source: The Scientist, Infographic: How Some X-Chromosome Genes Escape Inactivation  Epigenetics: The study of modifications of chromatin that may be heritable during mitosis mr sometimes during meiosis that affect gene expression without altering DNA sequences.  Example: DNA methylation patterns Genomic Imprinting: An epigenetic phenomenon that results in the differential expression of genes based on their parental origin. It involves the marking or "imprinting" of genes during gamete formation (sperm or egg cells) in such a way that the expression of specific genes is influenced by whether they were inherited Source: ChatGPT from the mother or the father. Epigenetics:  Different DNA methylation patterns in the maternal and paternal derived chromosomes. Imprinting  Mechanism often carried out by expression of Long Non-Coding RNA’s that silence the genes in the imprinted chromosomal region (as in X-inactivation)  Examples: Beckwith-Wiedemann syndrome, Angelman syndrome, Prader- Willi syndrome GeneReviews, Beckwith-Wiedemann Syndrome, Figure 1, © 1993-2023, University of Washington, Seattle. Genetic Counseling Genetics 2: Part 2 2009, Public Domain, Wikimedia Commons, File:Geneticcounseling.jpg  In accordance with the guidelines set forth in the syllabus, it is expected the student will: 1) Differentiate between screening, diagnostic, and predictive testing Lecture 2) Identify patients who would benefit from referral to a genetic counselor Objectives: 3) Counsel a patient on genetic screening and Genetic diagnostic testing options 4) Describe the difference in information obtained Counseling from a chromosome test versus a comparative genomic hybridization 5) Explain the term ‘variant of uncertain significance’ 6) Discuss psychosocial aspects of genetic counseling including ethics, privacy, financing, and follow-up  “Genetic Counseling is a communication process which deals with the human Definition problems associated with the occurrence, or the risk of occurrence, of a genetic disorder in a family.” Source: National Society of Genetic Counselors  The family or individual should  Comprehend the medical facts;  Appreciate the way heredity contributes to the disorder, and the risk of recurrence in specified Goals of relatives; counseling  Understand the alternatives for dealing with the risk of recurrence;  Choose the course of action;  Make the best possible adjustment to the disorder.  Provide information (as much as possible) Leave decision-making up to the Non-directive patient/family counseling Try not to inject your own opinions  Family goals  Religious/ethical standards  Prospective  Risks for future offspring, family members  Evaluate risks for transmitting a genetic Types of disorder counseling Retrospective  Evaluate/counsel people who may have a genetic condition.  Diagnosis, prognosis, treatment options  Genetic Screening  Test an entire population for pathologic genetic Differentiate variants between  Unrelated to whether someone is symptomatic screening,  Examples: diagnostic, and  Newborn screening (PKU, Cystic Fibrosis, Sickle Cell, etc.)  Purpose: Early Diagnosis and Treatment predictive  Carrier screening (Tay-Sachs, Sickle Cell, CF) testing  Purpose: Prenatal risk counseling  Disease risk screening (Cholesterol, Cancer genes)  Purpose: Early testing and intervention  Diagnostic Testing  Test symptomatic individuals to find the cause of their Differentiate disorders between  Confirms diagnosis and may guide treatment screening,  Examples: diagnostic, and  Cancer gene testing in people early onset colon or breast cancer predictive  Muscle gene testing in children with myopathy or testing cardiomyopathy  CFTR testing in individuals suspected of having cystic fibrosis  Predictive Testing Differentiate  Test asymptomatic individuals to find whether they are between at risk for later onset disorders. screening,  Goal: Early intervention, genetic counseling diagnostic, and  Examples predictive  Cholesterol levels to determine risk for heart disease  Cancer gene testing testing  Alzheimer disease risk genes  “What if you could combat aging and discover the full potential of the human body? Chris Hemsworth explores this revolutionary idea. Coming to Disney+ November 16.” NationalGeographic.com In Episode 5 ,“Memory”, results of a genetic test revealed that he is Chris homozygous for APOE4 variant of APOE, indicating a 10x higher risk for developing Alzheimer disease. Hemsworth, Limitless   Vanity Fair: In the fifth episode of the show, “Memory,” you don’t get a diagnosis, but you got…a warning? How would you characterize it?  Chris Hemsworth:Yeah, they took all my bloodwork and did a bunch of Chris tests and the plan was to on-camera tell me all the results and then talk about how you can improve this and that. And Peter Attia, who is the Hemsworth, longevity doctor in that episode, and overseeing a lot of the show, called [show creator] Darren [Aronofsky] and said, “I don't want to tell him this Limitless on camera. We need to have an off-side conversation and see if he even wants this to be in the show.” It was pretty shocking because he called me up and he told me.  How did that go?  It was a pretty brief conversation, all things considered. I hung up the phone and my parents were there, at the time. They were like, “What was that about?” And I told them, and then they had a bunch of questions. I had a bunch of questions, but no one answered them. I wish I'd had a more intense follow-up with it because I didn't really know what to think. I was like, “Am I supposed to be worried? Is this concerning?” Vanity Fair  Prospective Counseling Identify Affected individuals with a genetic patients who disorder or other medical condition would benefit  Risk that it might be transmitted to their children from referral Individuals with a positive family history to a genetic  Risk for themselves or for their children counselor Couples of "advanced" parental age  Prenatal diagnosis  Prospective Counseling Identify Known carriers of autosomal recessive disorders patients who  Carrier screening programs would benefit  Sickle cell anemia, Thalassemia, Tay-Sachs from referral Disease, CF  Prenatal diagnosis to a genetic Consanguineous couples counselor Teratogen exposure  Radiation, chemotherapy, medication Identify Prospective Counseling patients who Individuals who are "at risk" for an adult- would benefit onset genetic disorder from referral  Predictive genetic testing to a genetic People who want a screening test for counselor such disorders, even if not “at risk”.  Retrospective Counseling Affected individuals with a genetic disorder or other medical condition Identify  Medical counseling regarding the disorder patients who  Possible interventions would benefit Couples with a child with birth defects or potentially genetic disorder from referral Couples who have had multiple to a genetic miscarriages ( 2 or more ) stillbirths counselor Currently pregnant couples  maternal age, family history, or abnormal prenatal screening tests (especially maternal serum alpha-fetoprotein)  Accurate diagnosis Counsel a patient on Complete family history genetic Determine pattern of inheritance screening and Calculate genetic risk diagnostic Explain diagnosis/risk to family testing options Communicate with family’s physicians Describe the difference in information obtained from a chromosome test versus a comparative genomic hybridization Karyotype Requires living cells with nuclei Standard White blood cells Skin cells chromosome Bone marrow study Cells cultured to make them divide Chemicals added to hold them in division (chromosomes visible) Stained Analyzed with a microscope Requires skilled technician Describe the difference in information obtained from a chromosome test versus a comparative genomic hybridization (Chromosomal Microarray) Chromosomal microarray  Uses DNA segments attached to a silicon chip  DNA from any source  Does not need living cells  No culture or staining  Machine reads the chip  Analyzes chromosome number  Analyzes for missing pieces (deletions) or extra pieces (duplications)  Better resolution than standard chromosome study  Can find smaller changes (may not be significant)  Does not pick up balanced translocations 2014, WikiMedia Commons, Public Domain, US National Institutes of Health Explain the  A variant of unknown significance (VUS) refers to a specific genetic alteration or mutation detected during genetic testing whose clinical implications and association with a particular disease or condition are term ‘variant uncertain or not well-established.  When conducting genetic tests, such as DNA sequencing, researchers of uncertain and clinicians may come across genetic variants that do not have a clear correlation with a known disease or health condition. significance’  A VUS occurs when the detected variant's significance cannot be definitively determined based on the available scientific evidence and knowledge at that time. It means that the functional consequences of the variant and its potential impact on an individual's health or disease risk are not fully understood.  When a variant is classified as a VUS, it means that further research, studies, or additional evidence are required to determine its clinical significance.  As scientific knowledge and databases grow, it is possible that some VUSs may be reclassified into one of the other categories.  Genetic counselors and healthcare professionals typically provide additional information and guidance to individuals who have received a VUS result to help them make informed decisions about their health and medical management  Psychosocial issues play a significant role in genetic counseling, as Discuss the field encompasses not only the medical and scientific aspects but also the emotional, ethical, and social dimensions of genetic psychosocial information. Here are some key psychosocial issues that arise in the context of genetic counseling: aspects of 1.Emotional Impact genetic 2.Decision-Making counseling 3.Family Dynamics including 4.Stigma and Discrimination. ethics, privacy, 5.Ethical Issues financing, and 6.Cultural and Societal Influences 7.Psychological Support follow-up 8.Long-Term Psychological Outcomes Source: ChatGPT Discuss psychosocial Emotional Impact: Receiving genetic information aspects of about a potential risk for a genetic genetic condition can evoke a range of emotions, including counseling anxiety, fear, guilt, sadness, and uncertainty. Genetic counselors including need to be attuned to these emotional reactions and provide ethics, privacy, appropriate support and guidance to individuals and financing, and families. follow-up Source: ChatGPT Discuss Decision-Making: psychosocial Genetic testing often involves complex aspects of decisions, such as whether to undergo testing, which tests to pursue, and how to genetic interpret and act on the results. These decisions can be challenging due to factors counseling like potential impact on family members, reproductive choices, and psychosocial including implications. Genetic counselors assist ethics, privacy, individuals in understanding their options, exploring their values, and making informed financing, and decisions that align with their personal circumstances. follow-up Source: ChatGPT Discuss Family Dynamics: psychosocial Genetic information can have aspects of implications for multiple family members, and it may uncover genetic previously unknown relationships, carrier status, or counseling inherited conditions. Genetic counselors help individuals including navigate these dynamics, ethics, privacy, facilitating communication within families and addressing financing, and potential conflicts or tensions that may arise. follow-up Source: ChatGPT  Stigma and Discrimination: Discuss Some genetic conditions carry social stigma, and individuals psychosocial may fear discrimination in various domains, such as aspects of employment, insurance coverage, and personal genetic relationships. Genetic counselors can provide counseling information about the legal and ethical aspects of genetic including discrimination and offer guidance on how to cope with ethics, privacy, potential challenges. financing, and Are genetic variants “preexisting conditions” that follow-up affect eligibility for health insurance, life insurance, disability insurance, employment, etc. Source: ChatGPT Discuss Ethical Issues: psychosocial Genetic counseling involves aspects of ethical considerations, such as ensuring informed consent, genetic respecting autonomy, maintaining confidentiality, and counseling managing conflicts of interest. Genetic counselors must be including knowledgeable about ethical frameworks and guidelines to ethics, privacy, navigate these issues financing, and effectively. “Non-directive counseling” follow-up Source: ChatGPT  Cultural and Societal Discuss Influences: psychosocial Cultural beliefs, values, and societal norms can significantly aspects of influence individuals' genetic perceptions of genetic conditions, reproductive counseling choices, and decision-making. Genetic counselors should be including sensitive to cultural and societal factors and provide culturally ethics, privacy, competent care that respects diverse perspectives and financing, and supports informed decision- follow-up making within each individual's cultural context. Source: ChatGPT Discuss psychosocial Psychological Support: Genetic counseling often aspects of involves providing psychological genetic support to individuals and families as they grapple with the counseling emotional impact of genetic information. Genetic counselors including may collaborate with mental health professionals to address ethics, privacy, concerns such as anxiety, depression, grief, and financing, and adjustment difficulties. follow-up Source: ChatGPT  Long-Term Psychological Discuss Outcomes: psychosocial The impact of genetic information can extend beyond the immediate aspects of counseling session. Individuals may experience ongoing genetic psychological challenges related to coping with a genetic counseling condition, adjusting to life- altering decisions, managing the including uncertainty of future risks, or ethics, privacy, dealing with the loss of a loved one. Genetic counselors can financing, and provide resources for ongoing psychological support and help follow-up individuals access appropriate services as needed. Source: ChatGPT Discuss In summary, psychosocial psychosocial issues are integral to genetic counseling. Genetic counselors aspects of not only address the medical aspects of genetic information genetic but also provide emotional support, facilitate decision- counseling making, navigate ethical including considerations, and consider cultural and societal influences ethics, privacy, to ensure comprehensive care for individuals and families financing, and seeking genetic counseling services. follow-up Source: ChatGPT The End Genetics Lecture 2