Genetics (pedigree) help
gabybsanchez
PedigreeFamilyHistory.pptx
Why Family History?
Single-gene disorders:
Knowledge of family history can aid in the diagnosis and treatment of rare single-gene disorders such as cystic fibrosis, fragile X syndrome, Huntington disease, or familial hypercholesterolemia.
Common, complex diseases:
Family history has been shown to be a major risk factor for many chronic diseases such as cardiovascular disease, cancer, mental illness, and asthma.
Family history may be the primary risk factor!
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Pedigree Construction
In order to practice at a level demonstrating competency, the healthcare provider should ask family history questions that include a minimum of 3 generations.
4 generations is more common (patient, children, parents, grandparents)
The focus this week will be on pedigree construction and Mendelian inheritance patterns.
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Benefits of a Family History
Collect – Interpret - Intervention
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Family History
Inform diagnosis
Build rapport
with patients
Promote risk
assessment and
stratification
Change
management
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Benefits
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Single-gene disorders
Knowledge of family history can aid in diagnosis and treatment of rare single-gene disorders
Examples: cystic fibrosis, fragile-X syndrome, Huntington disease, or familial hypercholesterolemia
Common, complex diseases
Family history is a major risk factor for many chronic diseases
Examples: cardiovascular disease, cancers, mental illness, and asthma
Family history may be the primary risk factor
Pedigrees
Uses standard symbols and terminology to represent a large amount of information in a diagram
Preferred method of organizing and displaying family history
Least expensive genetic test!
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Benefits of Pedigree
Organize a great deal of family history information
Goal is minimal writing and being able to visualize if an illness/disease is tracking through a family
Visualizes inheritance pattern identifies red flags
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What Can Affect Your Construction and Interpretation of a Pedigree?
Missing information vs. unaffected individuals
Reliability of information
Non-traditional families
Unknown paternity
Adoption
Cultural definitions of family
Cultural biases
Consanguinity
Confidentiality
Penetrance
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Pedigree Nomenclature
Recognize, understand, and use standard pedigree symbols
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Bennett, et al. (2008)
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A Standardization Task Force of the National Society of Genetic Counselors. Am J Hum Genet, 56(3), 745-52.)
Bennett, et al. (2008). Journal of
Genetic Counseling, 17, 424-433.
Icons are All the Same Size
Vertical Lines are Offspring;
Siblings joined by 1 Horizontal Line
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Key Points
Standard Symbols are used when constructing a pedigree
Affected Male
Male
Female
Affected Female
Relationship
Line
Broken Relationship
Line
Line of decent
Consultand & Proband
Consultand
Arrow indicates Proband/ consultand
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(
Collection
Identification of the proband:
The proband is the affected individual who brings the family to medical attention
(A consultand is often also a proband)
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(
Construction
Gather family history to construct at least a 3-generation pedigree that includes
1st, 2nd, and 3rd degree relatives
Maternal and paternal relatives
Full and half relationships
Affected and unaffected relatives
Identify the historian, or person providing the information (may be patient or someone else, such as parent)
Date of construction
Name of person who constructed the pedigree
Legend or key of symbols used to indicate disease
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Confidentiality
Limit identifying information to maintain confidentiality and privacy
For clinical (non-published) pedigrees can include:
initials of proband/consultand
Initials of relatives for identification, as appropriate (or do not add at all due to HIPAA)
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In Pedigree and In Key
Use:
Different colors for different diseases, illnesses, or conditions
If more than 1 illness, divide icon in halves or quarters as needed
Symbols in key should be shaded to indicate the disease, illness, condition, or carrier status, etc. as part of the nomenclature
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When Taking a Family History
Ask information about all individuals
Age, birthdate, or year of birth
Relevant health information
Diagnosis, age at diagnosis
Age of death, or years of birth/death
Cause of death
Ethnicity for each biological grandparent
Consanguinity
Pregnancies
Pregnancy complications (note gestational age)
Miscarriages, stillbirths, ectopic pregnancies, pregnancy terminations, preterm births, preeclampsia, bleeding/clotting complications
Infertility, or no children by choice
Bennett et al. (2008)
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Pedigree Construction
Include Generation indicated by Roman Numerals
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I
II
III
IV
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A three-generation family typically begins with the patient’s generation and includes the parents and grandparents. If the patient and/or his or her siblings have children, the pedigree may be extended to include a fourth generation.
Asking about the patient’s maternal and paternal relatives gives us the basic structure of his or her family.
Pedigree Construction
Identify Individuals by Arabic Numbers (digits)
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I
II
III
IV
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2
4
1
2
3
5
4
6
5
3
1
2
3
4
6
7
8
1
2
3
4
5
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A three-generation family typically begins with the patient’s generation and includes the parents and grandparents. If the patient and/or his or her siblings have children, the pedigree may be extended to include a fourth generation.
Asking about the patient’s maternal and paternal relatives gives us the basic structure of his or her family.
Consanguinity Example
Note degree of
relationship
Bennett et al. (2008)
N
1st cousins
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Additional Standard Pedigree Symbols
Fraternal Twins
(dizygotic)
Identical Twins
(monozygotic)
Affected Individuals
Presymptomatic Carrier
Bennett et al. (2008)
Carrier
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Additional Standard Pedigree Symbols
Identical Twins
(monozygotic)
Affected Individuals
Presymptomatic Carrier
Bennett et al. (2008).
Carrier
KEY
Carrier of CF
Cystic fibrosis
Huntington’s Disease
Presymptomatic carrier of HD
E+
E+
ΔF508
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Pedigree Construction
Identification of patient (consultand or proband)
Patient’s 1st, 2nd, and 3rd degree relatives
Information on maternal and paternal relatives
Relationship no longer exists
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Pedigree Construction
Degree of relationship
Distinguish “full” from “half” relationships
Age, birth date, or year of birth
Relevant health information
Age at, or year of death
Cause of death
d. 70’s d. mid 60’s d. 55 yo d. late 60’s
“natural causes” dementia heart attack cancer (colon?)
35 yo 32 yo 30 yo
2 yo 5 mo 3 yo 6 yo 1.5 yo
“hole in heart”
40 yo 38 yo 35 yo
d. 54 yo 61 yo 55 yo 60 yo 59 yo 63 yo
accident depression lung cancer high cholesterol
## yo = Current age
d. = age at death, cause
dx@ = Age at diagnosis
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Pedigree Construction
Diagnosis, age at diagnosis
Affected and unaffected individuals
d. 70s d. mid 70s d. 55 yo d. late 60s
“natural causes” dementia, mid 60s heart attack ca. (colon?), late 60s
35 yo 32 yo 30 yo
2 yo 5 mo 3 yo 6 yo 1.5 yo
“hole in heart”
40 yo 38 yo 35 yo
d. 54 yo 61 yo 55 yo 60 yo 59 yo 63 yo
accident depression, lung ca., 58 yo high cholesterol
42 yo
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.
Pedigree Construction
Pregnancies
Pregnancy complications (note gestational age)
Infertility, or no children by choice
d. 70s d. mid 70s d. 55 yo d. late 60s
“natural causes” dementia, mid 60s heart attack ca. (colon?), late 60s
35 yo 32 yo 30 yo
2 yo 5 mo 3 yo 6 yo 1.5 yo
“hole in heart”
40 yo 38 yo 35 yo
d. 54 yo 61 yo 55 yo 60 yo 59 yo 63 yo
accident depression, lung ca., 58 yo high cholesterol
42 yo
infertility by choice
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Pedigree Construction
Ethnicity for each biological grandparent
Consanguinity
d. 70s d. mid 70s d. 55 yo d. late 60s
“natural causes” dementia, mid 60s heart attack ca. (colon?), late 60s
35 yo 32 yo 30 yo
2 yo 5 mo 3 yo 6 yo 1.5 yo
“hole in heart”
40 yo 38 yo 35 yo
d. 54 yo 61 yo 55 yo 60 yo 59 yo 63 yo
accident depression, lung ca., 58 yo high cholesterol
42 yo
by choice by choice
*no consanguinity reported*
N. European German, English, American Indian
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(For more information on consanguinity, see: Bennett, R.L., Motulsky, A.G., Bittles, A., Hudgins, L., Uhrich, S., Doyle, D.L., Silvey, K., Scott, C.R., Cheng, E., McGillivray, B., Steiner, R.D., & Olson, D. (2002). Genetic Counseling and Screening of Consanguineous Couples and Their Offspring: Recommendations of the National Society of Genetic Counselors. J Genet Couns, 11(2), 97-119.)
Pedigree Construction
In key, symbols are used to designate disease
Name of collector and date
Key:
dementia Lung cancer
depression born with
“hole in heart”
Collected by: __________________
Collected on: __________________
Jane Doe
August 20, 2006
d. 70s d. mid 70s d. 55 yo d. late 60s
“natural causes” dementia, mid 60s heart attack ca. (colon?), late 60s
35 yo 32 yo 30 yo
2 yo 5 mo 3 yo 6 yo 1.5 yo
“hole in
heart”
40 yo 38 yo 35 yo
d. 54 yo 61 yo 55 yo 60 yo 59 yo 63 yo
accident depression, lung ca., 58 yo high cholesterol
42 yo
by choice by choice
*no consanguinity reported*
N. European German, English, American Indian
MI
Colon Ca
Hyper-
cholesterolemia
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Final Pedigree
Key:
dementia Lung cancer
depression hole in heart
Collected by: __________________
Collected on: __________________
Jane Doe
August 20, 2006
d. 70s d. mid 70s d. 55 yo d. late 60s,
“natural causes” dx.mid 60s dx. late 60s
35 yo 32 yo 30 yo
2 yo 5 mo 3 yo 6 yo 1.5 yo
40 yo 38 yo 35 yo
d. 54 yo 61 yo 55 yo 60 yo 59 yo 63 yo
accident dx. 42 yo dx.58 yo
N. European German, English, American Indian
MI
Colon Ca
Hyper-cholesterolemia
I
II
III
IV
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2
3
2
1
3
4
1
2
3
4
5
4
5
6
3
4
6
7
8
1
2
5
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What your pedigree should look like
Red Flag Indications for Genetic Referral
F-GENES
Family history
Group of congenital anomalies
Extreme or exceptional presentation of common conditions
Neurodevelopmental delay or degeneration
Extreme or exceptional pathology
Surprising laboratory values
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F-GENES
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F: Family history
Multiple affected siblings or individuals in multiple generations
Family history of known or suspected genetic condition
Consanguinity (blood relationship of parents)
Ethnic predisposition to certain genetic disorders
Remember that lack of a family history does NOT rule out genetic causes
G: Group of congenital anomalies
Common anatomic variations
2 or more anomalies may indicate the presence of a syndrome
One or more major malformations
F-GENES
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E: Extreme or Exceptional pathology
Unusual tissue histology (pheochromoctyoma, acoustic neuroma, medullary thyroid cancer, multiple colon polyps, plexiform neurofibromas, multiple exostoses)
Most pediatric malignancies
S: Surprising Laboratory Values
Transferrin saturation of 65%
Potassium of 5.5 mmol/L
Sodium of 128 mmol/L in an infant
Cholesterol of >500 mg/dL and unconjugated bilirubin of 2.2 mg/dL in an otherwise healthy 25-year-old
Phosphate of 2 mg/dL and glucose of 35 mg/dL in a 6-month-old
Interpretation of Pedigrees
Multifactorial disorders
Multiple genetic and environmental factors
Mitochondrial disorders
Characterized by maternal transmission
Usually neurological or neuromuscular symptoms
Recognize basic inheritance patterns
Single-gene disorders
Autosomal Dominant
Autosomal Recessive
X-Linked
Chromosomal disorders
Extra/missing chromosomes
Large-scale deletions or duplications
Translocations
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Recessive
Homozygotes must have two copies of the altered gene/allele to be affected
Dominant
These individuals are called Heterozygotes with one copy of the altered gene/allele they are affected
X-linked recessive
Males with an altered gene on the X chromosome are always affected
Male
(X-linked dominant - Rare and usually lethal in males)
Single-Gene Disorders
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Hetero means ‘different’, homo means ‘same’
Homozygotes – received an affected chromosome from each parent who may have been healthy unaffected carriers
X-linked – always affected as they don’t have an X to balance the affected chromosome
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Single Gene Disorders
BRCA2
BRCA1
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Single-Gene Inheritance
Autosomal recessive
Two alleles necessary
Appears to “skip” generations
Male and female equally affected
Each parent must provide one allele
1-in-4 (25%) chance of homozygous transmission
Examples
Sickle-cell disease
Cystic fibrosis
Phenylketonuria (PKU)
Congenital deafness
Spinal muscular atrophy
Maple syrup urine disease
Single-gene Inheritance
Autosomal Recessive
Carrier
Example:
Sickle Cell Disease
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is referred to as “heterozygous.” The term “homozygous” refers to when both copies of the gene are identical.
Autosomal Recessive
Single-Gene Inheritance
Autosomal dominant
Single allele
50% chance of inheritance
male and females equally affect
does not “skip” a generation
Homozygous – rare, usually lethal
Examples
Marfan syndrome
BRCA1 and BRCA2
Huntington disease
Neurofibromatosis Type 1
Familial Hypercholesterolemia
Familial Adenomatous Polyposis (FAP)
Prader-Willi Syndrome
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Autosomal Dominant
Single-Gene Inheritance
X-Linked Recessive
Gene causing disorder is on X-chromosome
Expressed in males (one X-chromosome)
Variant degree of clinical expression in females depending on X-inactivation
Examples:
Duchenne Muscular Dystrophy
Fragile-X
Hemophilia
G6PD
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Single-gene Inheritance
X-Linked
Example:
Hemophilia (X-Linked Recessive)
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X-Linked
Multifactorial Inheritance
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The additive effects of 2 or more genes leading to a continuous variation rather than the either /or of a single gene
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Inheritance controlled by many genes plus the effects of the environment
Single gene disorders are quite rare
Single gene disorders either give risk to a condition or they do not
Most traits are polygenic, i.e., 1 trait coded by a number of altered and unaltered genes working together
Adult onset disorders of multifactorial inheritance
Diabetes mellitus
Epilepsy
Glaucoma
Hypertension
Ischemic heart disease
Manic depression
Schizophrenia
Multifactorial Inheritance
Familial Clustering
alcoholism d. suicide anxiety/ depression
depression
ADHD
mood disorder
Example: Alzheimer, Parkinson’s, ALS, IBS
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Nussbaum, R.L., McInnes, R.R., & Willard, H.F. (2004). Thompson and Thompson, Genetics in Medicine: Sixth Edition, Revised Reprint. Philadelphia: Elsevier Saunders.
Chromosomal Abnormalities
Some medical conditions are caused by abnormalities in chromosome number or structure
Most frequent numerical anomalies
Down syndrome (trisomy 21)
Edwards syndrome (trisomy 18)
Patau syndrome (trisomy 13)
Turner syndrome (45,X)
Klinefelter syndrome (47,XXY)
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Chromosome abnormalities was covered in “DNA, genes and chromosomes” presentation in lesson 1. The next 3 slides provides a refresher of the previous lesson.
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Chromosomal Translocation
Chromosomal abnormality in which a chromosome breaks and a portion of it reattaches to a different chromosome
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Family History Tools
My Family Health Portrait (Surgeon General’s Family History Initiative): https://phgkb.cdc.gov/FHH/html/index.html
U.S. Surgeon General Form: http://www.geneticsinprimarycare.org/YourPractice/Documents/US%20surg%20gen.pdf
Computer and iPad app: https://www.invitae.com/en/familyhistory/
Family History Resources and Tools (Centers for Disease Control and Prevention): www.cdc.gov/genomics/famhistory/
AMA Adult Family History Form https://www.ama-assn.org/delivering-care/collecting-family-history
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Pediatric Family History Tools
March of Dimes Family Health History Questionnaire: http://www.marchofdimes.org/pregnancy/your-family-health-history.aspx
Genetics in Primary Care Institute (GPCI): A toolkit to improve care for pediatric patients with genetic conditions in primary care: https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/Pages/Genetics-in-Primary-Care-Institute.aspx
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How to Find a Genetic Professional
National Society of Genetic Counselors www.nsgc.org
American Society of Human Genetics www.ashg.org
National Cancer Institute http://www.cancer.gov/cancertopics/genetics/directory
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Family history is key
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Questions???
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