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13 Using a Pedigree to Explore a Patient’s Understanding and to Clarify Misconceptions
THE LANGUAGE OF THE PEDIGREE
Common Patient Misconceptions and Beliefs about Inheritance
Ø If no one else in the family is affected, the condition is not inherited.
Ø If several people in the family have the same condition, it must be inherited.
Ø All birth defects are inherited.
Ø The parents (particularly the mother) must have done something before conception or
during the pregnancy to cause the condition in their fetus or child.
Ø An external event caused the problem (such as radiation from ﬂying in airplanes, living near
a power line or a nuclear reactor, a lunar eclipse).
Ø An evil spirit or an angered ancestor caused the disease.
Ø With a 25% recurrence risk, after one affected child, the next three will be unaffected.
Ø With a 50% recurrence risk, every other child is affected.
Ø The disease skips a generation.
Ø Birth order inﬂuences disease status (for example, only the eldest or youngest child can be
Ø If the affected individuals in the family are all women, the condition must be sex-linked.
Ø A person will inherit the genetic condition because he or she looks or acts like the affected
relative(s). Or the opposite—a person will not inherit a condition because he or she bears
no resemblance to the affected relative(s).
Ø For a condition with sex-inﬂuenced expression (such as breast cancer), individuals of the
opposite sex cannot transmit the condition (for example, a male cannot pass on a gene
alteration for breast cancer).
Source: Modiﬁed from Connor and Ferguson-Smith, 1997.
The symbols of a genogram are construed similar to a pedigree (with males as
squares and females as circles), with usually three generations pictured. Pertinent
relationships are further described by communication lines that connect the symbols
(McGoldrick et al., 1999):
== Close, open communication with few secrets.
≡≡ Very close or fused; open communication without secrets.
∧∧∧∧ Poor communication, conﬂictual, many disagreements and secrets.
...... Distant communication (may be from geographic or lifestyle differences).
Estranged or cut off (no communication; may be from conﬂict or separation
such as divorce).
#### A relationship can be both close and conﬂictual (a double line with a zigzag
A sample genogram is shown in Figure 1.4 deduced from the ﬁctional families of
Harry Potter and Ron Weasley from the acclaimed book series by J. K. Rowling.
Pedigrees also often include information about levels of communication but not
in the explicit format of a genogram. For example it may be noted on a pedigree that
a person is adopted and has no contact with his or her birth family or that a person
is estranged from certain relatives. In general, genograms seem most useful for a
Neville is a good friend of
Neville Harry’s at school; he
eventually because a
professor of herbology.
Harry’s best friend is Ron
Weasley. He is also very close
to Hermione Granger.
Genogram of the ﬁctional families of Harry Potter and Ron Weasley from the J. K. Rowling Harry Potter series. (Illustration courtesy of Leslie
35 y Harry
b. July 31
Bellatrix Lestrange tortures Nevelle’s
parents until they become insane,
they now reside at St Mango’s
hospital for Magical
The Weasleys are
Harry’s family since his
parents are deceased.
Bellatrix LeStrange killed Sirius
Black at the Ministry of Magic
during a duel.
James Potter and
Sirius Black were best
friends at school.
Harry and his aunt Petunia despise
each other, but it is her home that
protects him from Lord Voldemort.
Harry are rivals
all throughout their
school years at Hogwarts
School of Withcraft and Wizardry.
THE LANGUAGE OF THE PEDIGREE
therapist’s chart or process notes when working with a client in long-term therapy;
this documentation is traditionally not part of a patient’s common medical record that
is shared with other health professionals. As construed currently, a genogram is not as
multifunctional as a pedigree, particularly for disease risk assessment and informing
strategies for genetic testing. The crisscross effects of the multiple communication
lines of a genogram may actually clutter the family graphic to the extent that it
becomes difﬁcult for the clinician to attend to the most relevant health information
for that ofﬁce visit.
Ecomaps are also a tool used primarily in personal and family therapy. The format
resembles a wheel, with the client in the center, and the social relationships (some of
which are also biologic) and agencies (such as church, employer, etc.) are in a circle
surrounding the client. The clients “circle of life” may include his or her employer,
teacher, sports coach, church and/or religious leader, friend, neighbor, and relatives
(partner or spouse, children, parents, etc.). The “spokes” of the wheel are similar to
the communication lines of genograms, showing them as close, conﬂictual, distant,
etc. (Rempel et al., 2007). The Ecomap is then used to assess the client’s or family’s support network. Consideration of how this approach may piggy-back with a
traditional genetic pedigree is a future area of research (Kenen and Peters, 2001). A
sample ecomap is shown in Figure 1.5 using information on the professional soccer player David Beckham (http://en.wikipedia.org/wiki/David Beckham; http://en.
wikipedia.org/wiki/Victoria Beckham; http://www.davidbeckham.com/; http://la.
The professional genetics organizations should coordinate efforts with the professional societies of family therapists and those of family practice practitioners (such
as nurses, physicians assistants and physicians) to consider the potential beneﬁts of
melding pedigrees and genograms (and possibly ecomaps) into a standardized format. There is a tricky balance between recording enough information to make the
family diagram useful and including so much information that the graphic can no
longer be quickly and concisely interpreted. The pedigree’s utility lies in its ability to simply and graphically depict complex information so that disease patterns
and risks, and biological relationships are immediately and obviously visible. The
pedigree can already be used as a psychosocial assessment tool as discussed in
1.15 THE CONTINUING EVOLUTION OF THE PEDIGREE IN THE AGE
OF GENOMIC MEDICINE
Genomics describes the study of the interactions among genes and the environment
(Guttmacher and Collins, 2002). The ability to practice genomic medicine by potentially viewing the molecular status of each patient’s individual genome has an effect
on all medical disciplines. Yet it is absurd to think that a complete genomic reference
map will then lead to the understanding of all that is human or that we are all the
direct and inevitable consequence of our genome. The genetic family history will
continue to play an essential role in the medicine of the 21st century. As Reed Pyeritz
David & Victoria
Figure 1.5 Ecomap of professional soccer player David Beckham, based on information from the public domain as of February 2009. (Illustration
courtesy of Leslie Ciarleglio.)
THE LANGUAGE OF THE PEDIGREE
(1997), former president of the American College of Medical Genetics succinctly
The importance of the family history will only be enhanced in the future. Even when
an individual’s genome can be displayed on a personal microchip, interpreting that
information will depend in large part on the biological and environmental context in
which the genome is expressed, and the family milieu is as good a guide as any.
Physicians can help deﬁne those contexts through careful family and social histories.
How those histories can be obtained and interpreted, when the average time for patient
interaction with a physician continues to diminish, are crucial areas for research.
Variation is the hallmark of humans—even within well-established diseases with
known patterns of inheritance, there is remarkable disease variability. Pedigree assessment will continue to play a critical role in our understanding of gene expression.
A patient who has a genetic disorder or one who carries a genetic susceptibility mutation cannot be viewed in isolation from the background of his or her family history.
How is it that ﬁve relatives with the same gene mutation can all have different ages of
disease onset and varying clinical manifestations of the same genetic disorder? The
patient and his or her genotype must be examined in the context of his or her genetic
and environmental exposures. The clues from buried ancestors can reach out to the
present to provide solutions for the future.
American College of Obstetricians and Gynecologists. (1987). Antenatal Diagnosis of Genetic
Disorders. ACOG Technical Bulletin 108. Washington, DC: ACOG.
American Society of Clinical Oncologists. (1997). Resource document for curriculum developing in cancer genetics education. J Clin Oncol 15:2157–2169.
Bennett RL, Steinhaus KA, Uhrich SB, O’Sullivan C. (1993). The need for developing standardized family pedigree nomenclature. J Genet Couns 2:261–273.
Bennett RL, Steinhaus KA, Uhrich SB, et al. (1995). Recommendations for standardized
human pedigree nomenclature. Am J Hum Genet 56 (3):745–752.
Bennett RL, Steinhaus French K, Resta RG, Lochner Doyle D. (2008). Standardized pedigree
nomenclature: Update and assessment of the recommendations of the National Society of
Genetic Counselors. J Genet Couns 17(5):424–433.
Center for Applied Research. (2008). Mini case study: Nike’s “Just Do It” Advertising Campaign: RES3:990108. Available at www.cfar.com/Documents/nikecmp.pdf. Accessed July
Childs B. (1982). Genetics in the medical curriculum. Am J Med Genet 13:319–324.
Connor M, Ferguson-Smith M. (1997). Essential Medical Genetics. 5th ed. Oxford: Blackwell
Erlanger MA. (1990). Using the genogram with the older client. J Mental Health Couns
Galton F. (1889). Natural Inheritance. London: Macmillan.
Gross SJ, Pletcher BA, Monaghan KG, Professional Practice and Guidelines Committee.
(2008). Carrier screening individuals of Ashkenazi Jewish descent. Genet Med 10(1):54–56.
Guttmacher AE, Collins FS. (2002). Genomic medicine—A primer. N Engl J Med 347(19):
Kenen R, Peters J. (2001). The colored, eco-genetic relationship map (CEGRM): A conceptual
approach and tool for genetic counseling research. J Genet Couns 10(4):289–301.
Mazumdar PMH. (1992). Eugenics, Human Genetics and Human Failings. London and New
McCarthy Veach P, LeRoy B, Bartels D. (2003). Facilitating the Genetic Counseling Process:
A Practice Manual. New York: Springer.
McGoldrick M, Gerson R, Shellenberger S. (1999). Genograms: assessment and intervention,
2nd ed. New York: Norton.
NCHPEG: National Coalition for Health Care Professional Education in Genetics.
(2007). Core Competencies in Genetics for Health Professionals, 3rd ed. Available at
www.nchpeg.org/core/core comp English 2007.pdf. Accessed July 5, 2008.
Online Mendelian Inheritance in Man, OMIM. Available at www.ncbi.nlm.nih.gov/omim.
Accessed July 5, 2008.
Pyeritz RE. (1997). Family history and genetic risk factors. Forward to the future. JAMA
Rempel GR, Neufeld A, Kushner KE. (2007). Interactive use of genograms and ecomaps in
family caregiving research. J Fam Nurs 13:403–419.
Resta RG. (1993). The crane’s foot: The rise of the pedigree in human genetics. J Genet Couns
Resta RG. (1995). Whispered hints. Am J Med Genet 59:131–133.
Rogers J, Durkin M. (1984). The semi-structured genogram interview: I. Protocol, II. Evaluation. Fam Systems Med 2:176–187.
Rose R, Humm E, Hey K, et al. (1999). Family history taking and genetic counseling. Fam
Steinhaus KA, Bennett RL, Uhrich SB, et al. (1995). Inconsistencies in pedigree nomenclature in human genetics publications: A need for standardization. Am J Med Genet
Stone Ml, ed. (1998). Screening and Early Detection of Gynecologic Malignancies. Update
Vol. 23. Washington, DC. American College of Obstetricians and Gynecologists.
No genetic factor works in a void, but in an environment which may help or hinder
—Eliot Slater (1936)
2.1 A TRIBUTE(ARY) TO MENDEL
In some far-off recess of the human mind hides the Mendelian rules of inheritance that
we learned in our early school education. While Mendelian patterns of inheritance
remain a foundation for understanding many genetic principles, like many ideas of
the 1860s, the principles of Gregor Mendel do not reﬂect the changing times. Should
we be surprised that inheritance patterns in humans are more complex than those in
garden peas or that an Augustinian monk is an unlikely resource in matters of human
Mendel’s laws work under the simple assumption that genetic factors are transmitted from each parent as discrete units that are inherited independently from one
another and passed, unaltered, from one generation to the next. Thus begin the
tributaries from Mendelian principles. We now know that genes do not function in
isolation, but interact with each other and the environment (for example, modifying
genes and regulating elements of genes). Genes that are in close proximity to each
other may be inherited as a unit rather than independently (such as contiguous gene
syndromes). Some genes are indeed altered from one generation to the next, as is evidenced by dynamic mutations (seen in trinucleotide repeat disorders), new mutations,
and parental imprinting. Chemical markers on our genomes’ DNA sequences actually change as we age without changing the actual sequence (epigenetics). Mendelian
principles really do not apply when applied to mitochondrial inheritance because, in
The Practical Guide to the Genetic Family History, Second Edition, by Robin L. Bennett
Copyright C 2010 John Wiley & Sons, Inc.
A BRIEF GENETICS PRIMER
this instance, there is virtually no paternal genetic contribution, and in uniparental
disomy where only one parent contributes the homologous chromosomes (or segment
of chromosomal material).
Despite these caveats, it is still useful to divide hereditary conditions into three
classic inheritance patterns: single gene (classic Mendelian), multifactorial and polygenic, and chromosomal. Single-gene disorders are classiﬁed by whether they are
dominant or recessive and by their locations on the chromosomes. Genes for autosomal disorders are on one of the 22 pairs of non-sex chromosomes (autosomes). Genes
for sex-linked disorders are on the X and Y chromosomes. Sporadic inheritance usually refers to the one-time occurrence of a condition. In these instances, unaffected
siblings usually do not have affected children but the parents of the affected child
may have a risk of recurrence due to factors such as gonadal moscaicism and parental
Clues for identifying the standard and not-so-standard patterns of inheritance are
reviewed in Table 2.1. This chapter includes representative pedigrees for the primary
inheritance patterns as well as tables with a sampling of common genetic conditions
and their estimated incidences (Tables 2.2–2.4).
2.2 A BRIEF GENETICS PRIMER
This is a cursory review of some principles of human genetics. I have chosen points
that may be useful to recall when one is interpreting family history information and
genetic test results.
Humans carry an estimated 30,000 expressed genes. Genes are the basic chemical
unit of heredity. They are packaged in rows (like beads on a string) on rod-like
structures called chromosomes in the cell nucleus. Each gene has a speciﬁc place
or locus on the chromosome. Every person inherits one copy of a gene from his (or
her) mother and one from the father. Alternative copies of the same gene are called
alleles. Although any single person has only two alleles of a gene (one from each
parent), there may be many different types in the population. For example, in the
genes for hereditary breast-ovarian cancer syndrome (BRCA1 or BRCA2) there are
over 1,000 different gene mutations that can occur in each gene. The genotype is an
individual’s genetic constitution. The phenotype is the observed expression (physical,
biochemical, and physiological) of an individual’s genotype.
Humans have 23 pairs of chromosomes in each cell of the body, except the egg and
sperm, which have only one copy of each chromosome. There are 22 pairs of non-sex
chromosomes called autosomes. The 23rd pair of chromosomes, the sex chromosomes, are called X and Y. Females have two X chromosomes. Males have an X and
a Y chromosome. The centromeres are the sites of attachment of the spindle ﬁbers during cell division. A centromere divides a chromosome into a short (upper) arm called
the p arm and a long (lower) arm called the q arm. The telomeres are hot spots for
mutation and are the section of DNA or “caps” located at each end of the chromosome.
A gene is as a molecule of DNA (deoxyribonuclei acid). Four letters (representing
nitrogenous bases) in the DNA alphabet: A (adenine), C (cytosine), G (guanine), and
TABLE 2.1 Pedigree Clues for Distinguishing the Primary Patterns of Human
Males and females affected
Condition seen in multiple
Both males and females
Often see variability of clinical
Homozygotes may be more
severely affected than
Homozygous state may be
Sex-limited expression (e.g., if
individual has primarily male
relatives this makes it difﬁcult
to recognize an inherited
breast cancer or ovarian
Small family size may mask
Limited information about the
health of prior generations
may mask inheritance
Mild expression and/or late
onset of disease symptoms
may cause disease to be
New dominant mutation may
Gonadal mosaicism may cause
disease to be mistaken for AR
inheritance because parents
are unaffected but sibling are
Males and females affected
Affected individuals usually in
just one generation
Symptoms often seen in
newborn, infancy, or early
Often inborn errors of
Disease may be more common
in certain ethnic groups
Sometimes see parental
Small family size—may be
mistaken for sporadic
Males affected, may occur over
Females often express condition
but have milder
manifestations or later onset
Male-to-male transmission not
Some conditions have
embryonic male lethality so
might see many miscarriages
or paucity of males in
Small family size may mask
Limited knowledge about prior
generations may mask
May be missed if paucity of
males in family
Disorder may have high new
Gonadal mosaicism (in females)
A BRIEF GENETICS PRIMER
Males and females affected
Suspect in a person with two or more major
birth anomalies, or one major and two
minor birth anomalies, or three minor
Suspect in a fetus with a major structural
Unexplained intellectual disability (static,
nonprogressive), especially if associated
with dysmorphic features or birth anomaly
Unexplained psychomotor delays
Lymphadema or cystic hygroma in newborn
Multiple pregnancy losses
Family history of intellectual disability
Family history of multiple congenital
Unexplained infertility (male or female)
Males and females affected
Intellectual disability with other recognized
genetic or medical conditions
Recognized single-gene condition with
uncharacteristic dysmorphic features
Family history usually unremarkable
Males and females affected, often in
Father does not transmit condition, only
Highly variable clinical expressivity
Often nervous system disorders
May be degenerative
Males and females affected
No clear pattern
May skip generations
Few affected family members
T (thymine). Nucleotides are composed of a nitrogenous base, a sugar molecule, and
a phosphate molecule. The nitrogenous bases pair together—A with T, and G with
C—like rungs on a ladder, with the sugar and phosphates serving as the backbone. The
DNA ladder is shaped in a twisted helix. The DNA helix unzips and free nucleotides
join the single-stranded DNA to form a matching ribonucleic acid molecule called
messenger RNA (mRNA) in a process called transcription. The initial mRNA sense
strand matches the complementary anti-sense DNA template with the exception that
thymine (T) is replaced by uracil (U).
The DNA sequence has coding regions called exons that are interrupted by intervening sequences (IVSs), or introns. The DNA molecule also has regulatory regions
(such as those for starting and stopping transcription and translation) and specialized sequences related to tissue-speciﬁc expression. The initial mRNA (or primary
transcript) is modiﬁed before diffusing to the cytoplasm so that the ﬁnal mRNA is
composed of only exons (the IVSs are spliced out during the mRNA processing).
The mRNA molecule diffuses to the cytoplasm, where it is translated into a
polypeptide chain by the ribosomes. Each mRNA codon is recognized by a matching
complementary tRNA anticodon that is attached to a corresponding amnio acid. For
example, the DNA sequence GCT is transcribed into the mRNA sequence CGU. The
mRNA sequence CGU is read on the ribosomes by the tRNA anticodon GCA, which
attaches the amino acid arginine to the growing polypeptide chain. The sequence of
the 20 amino acids determines the form and function of the resulting protein (e.g.,
structural protein, enzyme, carrier molecule, receptor molecule, hormone). Proteins
usually undergo further modiﬁcation after ribosomal translation (e.g., phosphorylation, proteolytic cleavage, glycosolation).
Each cell contains hundreds of mitochondria in the cytoplasm. Mitochondria are
the powerhouses of the cells and are essential for energy metabolism. Each mitochondrion has about 10 single copies of small, circular chromosomes. These chromosomes
consist of double-stranded helices of DNA (mtDNA). Human mtDNA has only exons,
and both strands of DNA are transcribed and translated. The mitochondria behave as
semi-autonomous organisms within the cell cytoplasm with their own self-replicating
genome and replication, transcription, and translation systems.
All mitochondria are maternally inherited. The mitochondria in each cell are
derived at the time of fertilization from the mitochondria in the cytoplasm of the
ovum. There are about 100,000 mitochondria and mtDNA in the ovum and about 100
mtDNA in the sperm. The sperm mtDNA are degraded on entrance into the oocyte
(Wallace et al., 2007).
2.3 TYPES OF MUTATIONS
Understanding the ways genes can be changed is helpful in interpreting a test result
for your patient or when interpreting medical records on relatives. There are many
ways the genetic code can be altered. Part of the code for a gene can be deleted or a
change can be inserted. Pieces of the gene can be swapped between chromosomes (a
Point mutations alter the genetic code by changing the letters in the codons; this
change can mean the protein is not made or too much or not enough protein is
made. Frameshift mutations cause the DNA message to start in the wrong place. For
example, if the normal instruction to code for the amnio acid and thus the protein
is CAT EAT THE RAT, a frameshift mutation might be CAE ATT HER ATS. A
mutation at the end of the gene in the stop codon prevents the protein from being
made: CAT EAT THE. If the mutation affects the mRNA splicing, a portion of the
message is missing, leading to a shortened protein: CAT THE RAT.
A missense mutation causes an amino acid substitution: CAT EAT THE HAM.
Missense mutations do not always affect the function of the gene. When the gene