Tải bản đầy đủ - 0 (trang)
13 Using a Pedigree to Explore a Patient’s Understanding and to Clarify Misconceptions

13 Using a Pedigree to Explore a Patient’s Understanding and to Clarify Misconceptions

Tải bản đầy đủ - 0trang

12



THE LANGUAGE OF THE PEDIGREE



TABLE 1.2



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

affected.

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

through it).

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



13



Narcissa



Sirius is

Harry’s

godfather.



Bellatrix

Lestrange



Figure 1.4

Ciarleglio.)



James



Fleur

de la

Coeur



Victoire



Bill



Arthur



Percy



Fred



George



Rose



Ron



Hugo



Hermione



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.



Charlie



Molly



WEASLEY



Genogram of the fictional families of Harry Potter and Ron Weasley from the J. K. Rowling Harry Potter series. (Illustration courtesy of Leslie



Lily



Ginny



Vern



DURSLEY



Lily Petunia



Albus

Severus



35 y Harry

b. July 31



James



POTTER



LONGBOTTOM



Bellatrix Lestrange tortures Nevelle’s

parents until they become insane,

they now reside at St Mango’s

hospital for Magical

Maladies.



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.



Sirius

Black



Harry and his aunt Petunia despise

each other, but it is her home that

protects him from Lord Voldemort.



Draco and

Harry are rivals

all throughout their

school years at Hogwarts

School of Withcraft and Wizardry.



Scorpius



Draco



Lucius



MALFOY



14



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.

galaxy.mlsnet.com).

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

Section 9.2.



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



15



LA Galaxy

Soccer

USA

2007–present



David Beckham

Soccer

Academy

London/

Los Angeles



David & Victoria

Beckham

Children's

Charity



Unicef



Charity Work:



DOB 5/2/75



David

Robert

Joseph

Beckham



Gary

Neville

Close

friend



Parents

David &

Sandra

Beckham



Son

Cruz

David

DOB 2/20/05



Son

Brooklyn

Joseph

DOB 3/4/99



Jay Leno

Tom

Cruise

Katie

Holmes



Neighbors:



Son

Romeo

James

DOB 9/1/02



Past situation



Energy flow



Stressful



Tenuous



Strong



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.)



Real Madrid

Soccer

Spain

2003–2007



English

National

Team

101 career

games



Manchester

United

Soccer

England

1993–2003



Victoria

Adams

Beckham

DOB 4/17/74

Married 7/4/99



Legend



16



THE LANGUAGE OF THE PEDIGREE



(1997), former president of the American College of Medical Genetics succinctly

summarized:

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.



1.16 REFERENCES

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

5, 2008.

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

Science.

Erlanger MA. (1990). Using the genogram with the older client. J Mental Health Couns

12:321–331.

Galton F. (1889). Natural Inheritance. London: Macmillan.



REFERENCES



17



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):

1512–1520.

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

York: Routledge.

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

278(15):1284–1285.

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

2(4):1284–1285.

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

Practice 16:78–83.

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

56(3):291–295.

Stone Ml, ed. (1998). Screening and Early Detection of Gynecologic Malignancies. Update

Vol. 23. Washington, DC. American College of Obstetricians and Gynecologists.



Chapter



2



Practical Inheritance

No genetic factor works in a void, but in an environment which may help or hinder

its expression.

—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

reproduction?

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.



18



A BRIEF GENETICS PRIMER



19



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

imprinting.

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



20



PRACTICAL INHERITANCE



TABLE 2.1 Pedigree Clues for Distinguishing the Primary Patterns of Human

Inheritance

Inheritance

Pattern



Pedigree Clues



Confounding Variables



Autosomal

dominant (AD)



Males and females affected

Condition seen in multiple

successive generations

Both males and females

transmit (male-to-male

transmission observed)

Often see variability of clinical

disease expression

Homozygotes may be more

severely affected than

heterozygotes

Homozygous state may be

embryonic lethal



Sex-limited expression (e.g., if

individual has primarily male

relatives this makes it difficult

to recognize an inherited

breast cancer or ovarian

cancer syndrome)

Small family size may mask

inheritance

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

unrecognized

New dominant mutation may

mask inheritance

Gonadal mosaicism may cause

disease to be mistaken for AR

inheritance because parents

are unaffected but sibling are

affected



Autosomal

recessive (AR)



Males and females affected

Affected individuals usually in

just one generation

Symptoms often seen in

newborn, infancy, or early

childhood

Often inborn errors of

metabolism

Disease may be more common

in certain ethnic groups

Sometimes see parental

consanguinity



Small family size—may be

mistaken for sporadic

occurrence



X-linked (XL)



Males affected, may occur over

multiple generations

Females often express condition

but have milder

manifestations or later onset

of symptoms

Male-to-male transmission not

observed

Some conditions have

embryonic male lethality so

might see many miscarriages

or paucity of males in

pedigree



Small family size may mask

inheritance

Limited knowledge about prior

generations may mask

inheritance

May be missed if paucity of

males in family

Disorder may have high new

mutation rate

Gonadal mosaicism (in females)



A BRIEF GENETICS PRIMER



TABLE 2.1



21



(Continued )



Inheritance

Pattern



Pedigree Clues



Chromosomal



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

birth anomalies

Suspect in a fetus with a major structural

defect

Unexplained intellectual disability (static,

nonprogressive), especially if associated

with dysmorphic features or birth anomaly

Unexplained psychomotor delays

Ambiguous genitalia

Lymphadema or cystic hygroma in newborn

Multiple pregnancy losses

Family history of intellectual disability

Family history of multiple congenital

anomalies

Unexplained infertility (male or female)



Contiguous

gene

(segmental

aneusomy)



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



Mitochondrial



Males and females affected, often in

multiple generations

Father does not transmit condition, only

mother does

Highly variable clinical expressivity

Often nervous system disorders

May be degenerative



Multifactorial



Males and females affected

No clear pattern

May skip generations

Few affected family members



Confounding Variables



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



22



PRACTICAL INHERITANCE



(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

translocation).

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



Tài liệu bạn tìm kiếm đã sẵn sàng tải về

13 Using a Pedigree to Explore a Patient’s Understanding and to Clarify Misconceptions

Tải bản đầy đủ ngay(0 tr)

×