Family history

Family History
1.Introduction to Terminology-
Genetics, Genomics, Epigenetics and
Family History
2.Pedigrees-Charts and Definitions
3.Value of Family History-Details to
Include and questions to ask
4.Twin Studies, Newborn Screening,
Population Genetics-Ethnic Health
Risks

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 4,090,000
2,240,000

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 Portrait
https://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 Exome
and Genome Sequencing to make recommendations about responsible
management of incidental findings when patients undergo exome or
genome sequencing

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
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

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

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.
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.
http://en.wikipedia.org/wiki/Copy-number_variation
Evan Eichler
http://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_ge
netics
Recessive trait
red hair or cystic fibrosis
Autosomal Dominant Traits
Huntingtons 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=hypermethylation
and red=hypomethylation).

Randy Jirtle
http://randyjirtle.com/
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.
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

Family History
1.Introduction to Terminology-Genetics,
Genomics, Epigenetics and Family
History
2.Pedigrees-Charts and Definitions
3.Value of Family History-Details to
Include and questions to ask
4.Twin Studies, Newborn Screening,
Population Genetics-Ethnic Health
Risks

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 Examples
Autosomal Dominant Autosomal Recessive
X linked recessive

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, hypotonia
ataxia
• 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

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

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

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

Family and Patient History
Does 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 East
If yes to the previous two questions, have you or your
partner been tested for thalassemia?
Yes______No______
Yes No
______ ______ Eastern European (Ashkenazi) Jewish
______ ______ French Canadian
If yes to the previous two questions, have you or your
partner been tested for Tay Sachs?
Yes______No______
Yes No
______ ______ African American, African, or Black
If yes to the previous question, have you or your
partner been tested for sickle cell anemia?
Yes______No______

Prenatal Screening Questionnaire
Filling out and printing this form prior to an
appointment with a geneticist or genetic counselor
would be helpful for the specialist.
Father of the Pregnancy
Name_______________________________________
_______________________________ DOB
(00/00/00)_____________________________ Age
_____________________________ Ethnic Origin /
Religion______________________________________
___________________
Occupation___________________________________
_______________________________ Mother of the
Pregnancy
Name_______________________________________
_______________________________ DOB
(00/00/00)_____________________________ Age
_____________________________ Ethnic Origin /
Religion______________________________________
___________________
Occupation___________________________________
_______________________________

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 Argininemia
Argininosuccinic aciduria
• Biotinidase deficiency
Carnitine palmitoyltransferase II deficiency
Carnitine uptake defect
Citrullinemia I (ASA synthetase deficiency)
Cobalamin A, B
Congenital adrenal hyperplasia
Congenital hypothyroidism
Congenital toxoplasmosis
Cystic fibrosis
Galactosemia
Glutaric aciduria type I
Homocystinuria
Hyperornithinemia, hyperammoninemia, homocitrullinemia syndrome Isovaleric acidemia
Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency Maple syrup urine disease
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency Methylmalonic acidemia
Mitochondrial acetoacetyl-CoA thiolase deficiency
Multiple acyl-CoA dehydrogenase deficiency
Multiple carboxylase deficiency
Phenylketonuria (PKU)
Propionic acidemia
Sickle cell disease/hemoglobin disorders
Trifunctional protein deficiency
Very 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 East Asia
http://scienceblogs.com/gnxp/2008/12/07/genetic-map-of-east-asia/
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 variation within Africa (and the world)
http://blogs.discovermagazine.com/gnxp/2010/08/genetic-variation-within-africa-
and-the-world/#.UaeP8JyGdsI

Atul Butte
http://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
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/im agerecords/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

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

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.

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 and Genomics
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.

Family history

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