Family history

Family History

1.Introduction to Terminology-Genetics, Genomics, Epigenetics and Family History

2.Pedigrees-Charts and Definitions3.Value of Family History-Details to

Include and questions to ask4.Twin Studies, Newborn Screening,

Population Genetics-Ethnic Health Risks

Genetics and Family History

Genotype does not equal Phenotype

• Your genotype is your complete heritable genetic identity; it is your unique genome that would be revealed by personal genome sequencing

• In contrast, your phenotype is a description of your actual physical characteristics..

Family History

Family reunions are a great opportunity to share family history information

Genealogy and Family History

•

In the United Kingdom, a society dedicated to discovering one’s ancestors is called a

“family history society.” In the United States, the same group is referred to as a

“genealogical society.”

• GenealogyFamily History

• Global monthly searches 4,090,0002,240,000

Family History

Genetics and Genomics

• Genetics is the study of heredity

• Genomics is defined as the study of genes and their functions, and related techniques.

• The main difference between genomics and genetics is that genetics scrutinizes the functioning and composition of the single gene where as genomics addresses all genes and their inter relationships in order to identify their combined influence on the growth and development of the organism.

My Family Health Portraithttps://familyhistory.hhs.gov/fhh-web/home.action

• Using My Family Health Portrait you can:

• Enter your family health history.

• Print your family health history to share with family or your health care worker.

• Save your family health history so you can update it over time.

• Talking with your health care worker about your family health history can help you stay healthy!

Family History

• Disease information from family members provides valuable insights into familial pathologies, including:

• Heart Disease, Diabetes, Asthma, Obesity, Infectious Diseases, Sexually Transmitted Diseases, Gut Diseases and Microbe ecology, Skin Disorders, Behavioral Disorders, Mental Diseases

• Family includes aunts, uncles and grandparents in addition to parents and siblings.

Human genetic variation is the genetic differences both within and among populations. There may be multiple variants of any given gene in the human population (genes), leading to polymorphism. Many genes are not polymorphic, meaning that only a single allele is present in the population: the gene is then said to be fixed. On average, biochemically all humans are 99.9% similar to any other humans (about 3 million base pair differences between any 2 people).

Note the log phase on the Y axis-

Genet Med. 2013 Jul;15(7):565-74. doi: 10.1038/gim.2013.73. Epub 2013 Jun 20.ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. In clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing, which emphasized the importance of disclosing the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exomeand Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing

A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes in a human. For example, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case we say that there are two alleles. As of 26 June 2012, dbSNP listed 53,558,214 SNPs in humans http://en.wikipedia.org/wiki/Single-nucleotide_polymorphism

A SNP is a single-letter change in DNA, part of the natural genetic variation within a population.Image courtesy of Lauren Solomon, the Broad Institute

OMIM is a comprehensive, authoritative compendium of human genes and genetic phenotypes that is freely available and updated daily. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, under the direction of Dr. Ada Hamosh. Its official home is omim.org.http://www.ncbi.nlm.nih.gov/omim

http://www.ncbi.nlm.nih.gov/omim

This variation accounts for roughly 12% of human genomic DNA and each variation may range from about one kilobase (1,000 nucleotide bases) to several megabases in size. CNVs contrast with single-nucleotide polymorphisms (SNPs), which affect only one single nucleotide base.

Copy-number variations (CNVs)—a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal number of copies of one or more sections of the DNA.

http://en.wikipedia.org/wiki/Copy-number_variation

Evan Eichlerhttp://www.gs.washington.edu/faculty/eichler.htm

http://www.nature.com/nature/journal/v464/n7289/full/nature08516.html

Single Gene Genetics

• Autosomal: the gene responsible for the phenotype is located on one of the 22 pairs of autosomes (non-sex determining chromosomes).

• X-linked: the gene that encodes for the trait is located on the X chromosome.

• Dominant: conditions that are manifest in heterozygotes (individuals with just one copy of the mutant allele).

• Recessive: conditions are only manifest in individuals who have two copies of the mutant allele (are homozygous).

• Mitochondrial: Maternal transmission, males do not pass on these genes

Recessive and Dominant Traits

Introduction to genetics http://en.wikipedia.org/wiki/Introduction_to_genetics

Recessive traitred hair or cystic fibrosis

Autosomal Dominant TraitsHuntingtons Disease

Epigenetics

• Epigenetics is the study of changes in gene expression caused by certain base pairs in DNA, or RNA, being "turned off" or "turned on" again, through chemical reactions. In biology, and specifically genetics, epigenetics is mostly the study of heritable changes that are not caused by changes in the DNA sequence; to a lesser extent, epigenetics also describes the study of stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. Unlike simple genetics based on changes to the DNA sequence (the genotype), the changes in gene expression or cellular phenotype of epigenetics have other causes, thus use of the term epi- (Greek: επί- over, outside of, around)

Epigenetics in Identical twins=changes with age

Chromosome regions with differential DNA methylation in young and old monozygous twins.Significant 3-year-old twins have a very similar DNA methylation (yellow).The 50-year-old twin pair shows abundant changes in the pattern of DNA methylation (green=hypermethylationand red=hypomethylation).

Randy Jirtlehttp://randyjirtle.com/

Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation. Robert A. Waterland and Randy L. Jirtle http://mcb.asm.org/content/23/15/5293.long

Virgin a/a females, 8 weeks of age, were assigned randomly to NIH-31 diet or NIH-31 supplemented with the methyl donors and cofactors folic acid, vitamin B12, choline chloride, and anhydrous betaine

Maternal dietary methyl supplementation and coat color phenotype of Avy/a offspring. Isogenic Avy/a animals representing the five coat color classes used to classify phenotype. The Avy alleles of yellow mice are hypomethylated, allowing maximal ectopic agouti expression. Avy hypermethylation silences ectopic agouti expression in pseudoagouti animals, recapitulating the agouti phenotype.

http://mcb.asm.org/content/23/15/5293.long

Family History





Pedigree Chart

• A pedigree chart is a diagram that shows the occurrence and appearance or phenotypes of a particular gene or organism and its ancestors from one generation to the next, most commonly humans, show dogs, and race horses.

Pedigree Example

Pedigree Examples

Autosomal Dominant Autosomal Recessive

X linked recessive

Family History





Value of a Medical Family History

• An accurate family history is a well established method to recognize genetic disorders and susceptibilities that may pose risks for future health problems. It remains one of the most powerful genetic tests to identify individuals at risk for inheritable disorders when laboratory tests are not available.


• The family history is an essential first step before discussing genetic testing with a patient. It can help to target services for patients with a strong family history of disease, formulate genetic testing strategies, customize preventative treatments, and identify carriers of a deleterious gene who have not yet manifested the specific disorder


• The family history can be used to identify single gene disorders or chromosomal abnormality that affect multiple family members. These disorders can be common (breast or colon cancer) or rare (cystic fibrosis).

• More frequently, the family history will identify families with increased susceptibility to disorders such as diabetes or hypertension.

What information to include for a family history

• Details on 1st, 2nd and 3rd degree relatives. Organize this information into a detailed family tree or pedigree to visualize how traits are clustering within families and moving through generations.

• For each family member include: age, ethnicity, relevant medical conditions and age of onset

Examples of “red flags” in family history

• Several closely related individuals affected with the same or related conditions. For example, Breast and ovarian cancer, colon and endometrial cancer, Diabetes, heart disease and hypertension. Thyroid cancer and colon polyps.

More “red flags” in a family history

• A common disorder with earlier age of onset than typical, especially if it occurs in multiple family members.

• Breast Cancer <age 45-50 years (premenopausal)

• Colon Cancer <age 45-50 years

• Prostate Cancer <age 45-60 years

• Vision loss <age 55 year

More “red flags” in family history

• Hearing loss <age 55-60 years

• Dementia <age 60 years

• Heart Disease <40-60 years

• Stroke <age 60 years

• Sudden death in someone who seems healthy

• Individual or couple with 3 or more pregnancy losses

• Medical problems in children of parents who are closely related (second cousins or closer)

Within an individual, look for

• A medical condition and dysmorphic features

• Developmental delay and/or physical birth anomalies

• Learning disabilities or behavioral problems

• Unexplained seizures

• Unexplained movement disorders, hypotoniaataxia

• Congenital/juvenile deafness, blindness or cataracts

Within an individual, look for

• Disproportionate short stature

• Unexplained infertility

How should the family history tree be interpreted?

• If a medical condition seems to run in the family, consult with a genetic professional (medical geneticist, genetic counselor or genetic nurse) to ensure the correct interpretation.

• When appropriate, refer to a genetic professional for counseling to help understand the disease risk, the availability of confirmatory tests, and types of interventions

• Remind the patient that patterns often indicate increased risk and do not necessarily predict certainty of developing a medical condition.

Are there any potential nonmedical concerns associated with a family

history?

• The personal nature of information needed for family history can raise concerns about discriminatory practices (work or insurance), confidentiality, and changes in family dynamics.

• There is also potential of psychological, social and economic consequences of labeling an individual at risk for disease. More information can be found at www.nhgri.nih.gov

http://www.nhgri.nihgov

How do I locate a genetic professional in my area?

Many hospitals and university medical centers have board certified medical geneticists, certified genetic counselors and advanced practical nurses in genetics on staff.

A fully searchable, international directory of genetic clinics and laboratories is available at the GeneTests Web site (www.geneclinics.org)

A directory of medical geneticists certified is also available at www.abmg.org

http://www.geneclinics.org

http://www.abmg.org

Where can I access more information on generating a family history?

• The CDC has started a family history public health initiative at www.cdc.gov/genomics/activities/famhx.htm

• Bennett RL. The Practical Guide to the Genetic Family History. New York, NY. Wiley-Liss, Inc 1999.

• A family history newsletter is available at the National Coalition for Health Professional Education in Genetics web site: www.nchpeg.org

http://www.cdc.gov/genomics/activities/famhx.htm

http://www.nchpeg.org

Where can I access more information on generating a family history?

• A national awareness campaign on the importance of family history information has been initiated by the American Society for Human Genetics, www.ashg.org

• the Genetic Alliance, www.geneticalliance.org

• And the National Society for Genetic Counselors, www.nsgc.org and the AMA, www.ama-assn.org/go/genetics

http://www.ashg.org

http://www.geneticalliance.org

http://www.nsgc.org

http://www.ama-assn.org/go/genetics

Family and Patient HistoryDoes your family or the father of the baby's family have the following ethnic background:Yes No______ ______ Southeast Asia, Taiwan, China, or the Philippines______ ______ Italy, Greece, or the Middle EastIf yes to the previous two questions, have you or your partner been tested for thalassemia? Yes______No______Yes No______ ______ Eastern European (Ashkenazi) Jewish______ ______ French CanadianIf yes to the previous two questions, have you or your partner been tested for Tay Sachs? Yes______No______Yes No______ ______ African American, African, or BlackIf yes to the previous question, have you or your partner been tested for sickle cell anemia?

Yes______No______

Prenatal Screening QuestionnaireFilling out and printing this form prior to an appointment with a geneticist or genetic counselor would be helpful for the specialist.Father of the PregnancyName______________________________________________________________________ DOB (00/00/00)_____________________________ Age _____________________________ Ethnic Origin / Religion_________________________________________________________ Occupation__________________________________________________________________ Mother of the Pregnancy Name______________________________________________________________________ DOB (00/00/00)_____________________________ Age _____________________________ Ethnic Origin / Religion_________________________________________________________ Occupation__________________________________________________________________

Family History





Twin Studies• The role of genetics with respect to traits is

often studied with identical twins.

• While environment and many genes often contribute to certain traits (behavior) the percentage due to genetics can be determined with analysis of identical twins

History of Twin Studies

• Twins have been of interest to scholars since early civilization, including the early physician Hippocrates (5th century BCE), who attributed similar diseases in twins to shared material circumstances,[citation needed] and the stoic philosopher Posidonius (1st century BCE), who attributed such similarities to shared astrological circumstances. More recent study is from Sir Francis Galton's pioneering use of twins to study the role of genes and environment on human development and behavior. Galton, however, was unaware of the difference between identical and DZ twins

Methods for Twin Studies

• The power of twin designs arises from the fact that twins may be either monozygotic (identical (MZ): developing from a single fertilized egg and therefore sharing all of their alleles) – or dizygotic (DZ: developing from two fertilized eggs and therefore sharing on average 50% of their polymorphic alleles, the same level of genetic similarity as found in non-twin siblings). These known differences in genetic similarity, together with a testable assumption of equal environments for identical and fraternal twins creates the basis for the twin design for exploring the effects of genetic and environmental variance on a phenotype

Newborn Screening in NH• New Hampshire Newborn Screening Program List of Conditions • Each baby born in New Hampshire is screened for the conditions listed below. This list is correct as of

July 1, 2007 but may change as conditions are added to or removed from the testing panel. If you have any questions, please contact the New Hampshire Newborn Screening Program at (603) 271-4225.

• 3-hydroxy-3-methylglutaryl-CoA lysase deficiency 3-methylcrotonyl-CoA carboxylase deficiency ArgininemiaArgininosuccinic aciduria

• Biotinidase deficiencyCarnitine palmitoyltransferase II deficiencyCarnitine uptake defectCitrullinemia I (ASA synthetase deficiency)Cobalamin A, BCongenital adrenal hyperplasiaCongenital hypothyroidismCongenital toxoplasmosisCystic fibrosisGalactosemiaGlutaric aciduria type IHomocystinuriaHyperornithinemia, hyperammoninemia, homocitrullinemia syndrome Isovaleric acidemiaLong chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency Maple syrup urine diseaseMedium-chain acyl-CoA dehydrogenase (MCAD) deficiency Methylmalonic acidemiaMitochondrial acetoacetyl-CoA thiolase deficiencyMultiple acyl-CoA dehydrogenase deficiencyMultiple carboxylase deficiencyPhenylketonuria (PKU)Propionic acidemiaSickle cell disease/hemoglobin disordersTrifunctional protein deficiencyVery long chain acyl-CoA dehydrogenase (VLCAD) deficiency

Newborn screening is an invaluable public health program.This September marked the 50th anniversary of newborn screening

Population Genetics

• Population genetics is the study of the distributions and changes of allele frequency in a population, as the population is subject to the four main evolutionary processes: natural selection, genetic drift, mutation and gene flow. It also takes into account the factors of recombination, population subdivision and population structure. Studies in this branch of biology examine such phenomena as adaptation and speciation.

Population genetics is the study of the distributions and changes of allele frequency in a population, as the population is subject to the four main evolutionary processes: natural selection, genetic drift, mutation and gene flow. It also takes into account the factors of recombination, population subdivision and population structure. Studies in this branch of biology examine such phenomena as adaptation and speciation.

Genetic map of Europe; genes vary as a function of distance http://blogs.discovermagazine.com/gnxp/2008/08/genetic-map-of-europe-genes-vary-as-a-function-of-distance/#.UadHgZyGdsI

Razib Khan, Gene Expression Blog/Discover

Genetic Map of East Asia

http://scienceblogs.com/gnxp/2008/12/07/genetic-map-of-east-asia/

Genetic variation within Africa (and the world)http://blogs.discovermagazine.com/gnxp/2010/08/genetic-variation-within-africa-and-the-world/#.UaeP8JyGdsI

http://blogs.discovermagazine.com/gnxp/2010/08/genetic-variation-within-africa-and-the-world/#.UaeP8JyGdsI

Differences in genetic risk among populations.Each population is ranked by risk, which is denoted by a color. Populations with the greatest risk are bright red, and those with the lowest risk are green. (A) Populations for East Asia and the Americas have lower genetic risk for type 2 diabetes than those from Africa and Europe. Genetic risk differentiation is sharply divided along major population migration events. Type 2 diabetes is represented by 16 SNPs. (B) Genetic risk for biliary liver cirrhosis is represented by 44 SNPs. Genetic risk peaks in East Asia and in the Karitiana population in South America. The background is a public domain world map from NASA Earth Observatory (http://eoimages.gsfc.nasa.gov/images/imagerecords/73000/73909/world.topo.bathy.200412.3×5400×2700.jpg);an interactive online tool is available at http://geneworld.stanford.edu using Google Maps technology.doi:10.1371/journal.pgen.1003447.g001 Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration

Atul Buttehttp://buttelab.stanford.edu/

Erik Corona, Rong Chen, Martin Sikora, Alexander A. Morgan, Chirag J. Patel, Aditya Ramesh, Carlos D. Bustamante, Atul J. Butte. (23 May 2013) Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration. PLoS Genetics, 2013; 9 (5): e1003447 DOI: 10.1371/journal.pgen.1003447

Genetic Risk World Map

The human disease network http://www.pnas.org/content/104/21/8685.abstract

(b) In the DGN, each node is a gene, with two genes being connected if they are implicated in the same disorder. The size of each node is proportional to the number of disorders in which the gene is implicated (see key). Nodes are light gray if the corresponding genes are associated with more than one disorder class. Genes associated with more than five disorders, and those mentioned in the text, are indicated with the gene symbol. Only nodes with at least one link are shown.

In the HDN, each node corresponds to a distinct disorder, colored based on the disorder class to which it belongs, the name of the 22 disorder classes being shown on the right. A link between disorders in the same disorder class is colored with the corresponding dimmer color and links connecting different disorder classes are gray. The size of each node is proportional to the number of genes participating in the corresponding disorder

Family History





Family History

• Family History should require only a few minutes to complete=perhaps 10 minutes and can be performed prior to a visit with the health care provider

• Websites exist to complete a family history using a pedigree chart https://familyhistory.hhs.gov/fhh-web/home.action

• Family reunions and holidays provide excellent opportunities to gather family information regarding diseases.

https://familyhistory.hhs.gov/fhh-web/home.action

In popular media and common speech, the words "genetic" and "genomic" are often used interchangeably. However, to a geneticist, these terms have specific meanings. To appreciate the difference, we must first understand something about the structure of genetic material.Genetic information is stored in the molecule DNA, which consists of a string of chemicals called bases. The order of bases on the string, called the "sequence", determines the meaning of the genetic message. A gene is a specific stretch of bases that provides instructions for making a particular product, such as a piece of a hormone or enzyme. Humans have many thousands of genes, spaced across the entire set of DNA, which is packaged into 23 pairs of chromosomes. However, there are many DNA sequences in-between genes that do not directly encode specific products. Some of these sequences modify the way that genes are expressed. Other sequences do not have a known function.So, "gene" refers to a specific sequence of DNA on a single chromosome that encodes a particular product. The word "genome" encompasses the entire set of genetic information across all 23 chromosome pairs, including all genes, as well as gene-modifying sequences, and all the stuff in-between.In the context of clinical and research settings, "genetic" testing refers to the examination of

specific bits of DNA that have a known function, usually in a protein-coding gene. Genetic testing requires that an investigator know which gene or genes to look at, based on some prior understanding of the underlying biological contribution to a trait or disease."Genomic" testing, on the other hand, looks for variations within large segments across the

entirety of genetic material, both within and outside known functional genes. Investigators don't usually need to have a target gene in mind or any prior knowledge of the underlying biology of a trait when doing genomic testing. However, genomic testing produces large amounts of data that must be processed to tease out genetic variants of significance to a particular trait.

Types of Genetic Transmission of Traits

• Autosomal Dominant-50% of offspring affected

• Autosomal Recessive (compound heterozygotes)

• X linked (often boys affected-only one X)

• Mitochondrial (maternal transmission)

Genetics is a term that refers to the study of genes and their roles in inheritance - in other words, the way that certain traits or conditions are passed down from one generation to another. Genetics involves scientific studies of genes and their effects. Genes (units of heredity) carry the instructions for making proteins, which direct the activities of cells and functions of the body. Examples of genetic or inherited disorders include cystic fibrosis, Huntington's disease, and phenylketonuria (PKU). Testing for PKU started 50 years ago as new born screening-Guthrie Test.Genomics is a more recent term that describes the study of all of a person's genes (the genome), including interactions of those genes with each other and with the person's environment. Genomics includes the scientific study of complex diseases such as heart disease, asthma, diabetes, and cancer because these diseases are typically caused more by a combination of genetic and environmental factors than by individual genes. Genomics is offering new possibilities for therapies and treatments for some complex diseases, as well as new diagnostic methods.

Genetics and Genomics

Family history

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