The Evolution of a Classic Genetic Tool

The young couple was puzzled when their obstetrician sent them to a genetic counselor. The reasonñthe man had several small, benign, lumpy lesions under his skin on various parts of his body. Because he knew of no other family members who had the peculiar lumps, the man had never worried that it might be something he could pass on to a child.

The genetic counselor, like the obstetrician, suspected that the man might have neurofibromatosis type 1 (NF1), an inherited condition that passes from affected parent to child with a 50% probability. The man could not only transmit the condition, but a child could be more severely affected than its father. In the child, the many tumors could become cancerous. However, a few lumps do not a definitive diagnosis make. The genetic counselor needed more information. Her first job was to determine whether other family members had the condition.

Because she had only the womanís medical records, the genetic counselor had to turn sleuth. And so as the couple talked, describing the manís family, she outlined a family pedigree. Quickly, a pattern of shapes and lines emerged, squares for males, circles for females, vertical lines for generations, horizontal lines connecting parents or, if raised above the symbols, indicating siblings.

Next, the counselor asked the man to consider other manifestations of NF1. Did other family members have brownish skin marks? Actually, quite a few did, and the counselor filled in their representative circles and squares on the pedigree. Two of the relatives with these so-called cafe-au-lait spots also had a light-colored patch in the iris of the eye. Called a Lisch nodule, the patch is also a sign of NF1. The pattern of filled-in symbols on the pedigree hit every generation, males and females, in precisely the pattern one would expect for a dominant disorder such as NF1. When the counselor obtained the manís medical records, she discovered that he had indeed been diagnosed with NF1 years ago, but because his case was mild, he had not paid much attention to it. With this information, combined with her knowledge of the disorder, she could effectively counsel the surprised couple that their unborn child had a 50% risk of inheriting NF1.

Today the pedigree is a staple of human genetics, depicting both family relationships and trait transmission. The first pedigrees, though, were strictly genealogical. The term pedigree was first used in the fifteenth century. It comes from the French pie de grue, meaning the craneís foot. Early family trees showed parents linked to their children with curved lines, and a diagram of a large family quickly came to resemble a birdís foot.

One of the first and most extensive pedigrees to show inheritance of an illnessñhemophiliañinvolved several European royal families dating back to Queen Victoria and the original mutation in the nineteenth century. An 1845 family pedigree follows inheritance of color blindness using musical notation, because the author, Pliny Earle, had access only to musical note-printing symbols, reports Robert G. Resta of the Swedish Medical Center (Seattle, Washington) in the November 1993 Journal of Genetic Counseling. Quarter notes depict color-blind females and half notes depict unaffected females. To represent males, the notes are altered to appear square. The eugenics movement of the early twentieth century, influenced by the rediscovery of Mendelís laws, led to construction of pedigrees that attempted to trace feeblemindedness, legal skill, artistic talent, prostitution, and criminality through families, without genetic data.

Today, a pedigree may be a hastily sketched pencil drawing of a small family or a sophisticated, computer-generated, information-packed chart of an extensive clan. "Clinically, it is the very first thing done, no matter what you suspect is going on with the patient. If you donít have a correct diagnosis or mode of inheritance, a research project using those families will never get a right answer, or might be misleading. Research in human genetics hinges on accurate pedigrees at the beginning of a clinical workup," says Margaret Wallace of the University of Florida in Gainesville. In 1983, as a graduate student alone one muggy May night at a computer screen at Indiana University, Wallace was the first member of the multicenter Huntington disease (HD) team to realize that a marker for the diseaseña certain DNA sequence signaling the disease geneís presenceñhad been found. Wallace also discovered the gene for NF1 in 1990.

Gene hunts depend upon large families to lead researchers to markers that can be used as steppingstones to locate a gene of interest on its chromosomeñthat is, to map it. The quest for the HD gene in particular inspires awe among many geneticists for its sheer enormity. "The whole story of HD depended on a pedigreeñthey wouldnít have been able to localize the gene without it," says William J. Keppler of Florida International University in Miami. The decade-long hunt focussed on a Venezuelan family descended from a Portuguese sailor believed to have introduced the disease-causing gene in the 1800s. That pedigree grew so large that it looks like wallpaper.

Of course, that pedigree required more than pencil and paper. "We used a high-powered computer. As long as a genetic connection could be made to the main chunk of the family, the program could handle it. The program spit out a 4000-member pedigree," says Wallace.

Other extensive pedigrees have led to the identification of disease genes. An eight-generation, 154-person pedigree including 51 relatives who have Alzheimerís disease helped establish that the disorder can be inherited. And recent reports of newly discovered colon cancer genes trace back to Eldon Gardnerís work at the University of Utah in Salt Lake City in 1947. He was alerted by a student to a woman whose three children and three grandchildren had colon cancer. After scrutinizing family records, noting other symptoms, and having various relativesí colons checked, Gardner described a syndrome that would be named after him, and he later led geneticists to identify the first of the cascade of abnormal genes that leads to some forms of colon cancer.

Although the pedigree is the starting point for todayís frequent reports of new gene discoveries, it faces challenges from both changing lifestyles and the molecular information deluge of the 1990s. Today, pedigrees must often transcend the so-called traditional family and embrace assisted reproductive technologies. For example, it would take an artist such as M.C. Escher to bend the vertical generation lines of a classical pedigree to accommodate Arlette Schweitzer, the South Dakota woman whose twins, Chad and Chelsea, were conceived in 1990 using her daughter, Cristaís, oocyte.

Surrogate mothers require distinguishing between genetic and gestational mothers. Pedigrees must also ideally identify sperm donors as genetic fathers in cases of artificial insemination. Serial relationships and the resulting blended families can complicate pedigree drawings, as can uncertain paternity. An adopted individual is shown as a family member, but in evaluating inherited illness, the absence of a genetic relationship must be indicated. The relationship is usually shown by enclosing the symbol for the adopted person in brackets and using a dashed line as a connection to the adoptive parents.

Adding to the challenge of representing new social trends and reproductive technologies is the fact that geneticists do not all write in the same language when constructing pedigrees. Different symbols may be used even within the same issue of a journal. To remedy this problem, in 1992 the National Society of Genetic Counselors conducted a pedigree survey, which led to establishment of a pedigree task force to select standards. Preliminary conclusions were sent to participating geneticists in August, and they were to be published in 1994.

The pedigree standards will be tested for two years, says Robin Bennett, of the University of Washington Medical Center in Seattle, who heads the effort to standardize pedigrees. Choices of standard symbols and the lines that connect them on the standardized pedigree are based on five factors: clarity, consistency, frequency of existing use in the genetics community, software compatibility, and flexibility in including assisted reproductive technologies and DNA data.

It appears that this standardization effort is long overdue. "We get lots of genetic fellows passing through the clinic, and I couldnít believe how differently people drew pedigrees! Then at a regional meeting in Asilomar two years ago, just for fun, we did a brief survey asking how counselors represent reproductive technologies, pregnancy, and miscarriage. We didnít expect to find a huge variation. But when we found that hardly anybody did it the same way as anybody else, we decided to pursue it further," says Bennett.

Bennett found 17 different symbols for pregnancy and 12 for spontaneous abortion. A common situationñvoluntary pregnancy terminationñis variously recorded as VTOP, TOP, TA, EAB, ET, or ETP. (Noting abortion is important when an Rh blood incompatibility could exist, because contact with fetal blood during the procedure sensitizes the womanís body so that she manufactures anti-Rh antibodies in subsequent incompatible pregnancies.) New pedigree standards abbreviate termination of pregnancy as TOP and symbolize it with a triangle with a slash through it. The triangle is shaded if the fetus has a diagnosed medical condition.

Standardized pedigrees will also include notation for presymptomatic diagnosis of late-onset inherited disorders. "A big improvement will be distinguishing between an obligate carrier of a recessive condition who will not get the disease [such as sickle cell disease or cystic fibrosis], and a so-called carrier of a disease [such as NF1 or HD] who is still asymptomatic. A person who will not develop the disease has a small dot in the middle of the pedigree symbol, whereas an asymptomatic carrier will have a line down the middle of the symbol, with no shading. When the person becomes affected, the symbol is shaded in," Bennett says. This replaces the traditional half-shaded symbol for an obligate carrier. The need to represent presymptomatic individuals has arisen from genetic testing.

Despite attempts at standardization, some researchers will probably continue to mold pedigrees to fit particular diseases. Presently, individual investigatorsí variations on the pedigree theme account for much of the discrepancy between published reports. Examples abound.

Consider a pedigree for colon cancer appearing in the March 1994 American Journal of Human Genetics. Symbols for individuals with colon cancer are completely shaded in, but symbols for relatives with a precursor growth, called adenomatous polyps, are shaded in the bottom half. Yet in the same journal, a paper on schizophrenia uses a different approach to distinguish degrees of illness. It completely shades symbols representing relatives hospitalized for severe psychosis, but it fills in the right half of symbols for mildly affected individuals.

In another instance, a special pedigree symbol is used to depict several disorders of hemoglobinñthe oxygen-carrying protein in red blood cells. The symbol for an individual is divided into four quadrants, in parallel to the four polypeptides comprising the protein portion of the hemoglobin molecule. Shading in the appropriate quadrant represents the site of the defect in the molecule.

Ironically, as clinicians are adding information to pedigrees, they are also taking measures to protect patientsí confidentiality, a standard part of health care delivery in general, and of medical genetics in particular, where an illness typically has repercussions beyond the individual. For example, in the only pedigree appearing in the 17 November 1993 issue of the Journal of the American Medical Association, which was devoted to updating physicians on human genetics research, triangles replace the squares and circles that usually denote males and females in the four most recent of the six generations depicted. The pedigree traces inheritance of neurofibromatosis type 2. The triangles are used, write researchers James Gusella and coworkers at Massachusetts General Hospital and the University of South Alabama (Mobile), "to protect their privacy and to disguise the pedigree in view of the diagnostic significance of the results presented." (It is common among genetic researchers to withhold presymptomatic diagnoses from individuals under the age of 18 unless parents request the information.) In the same issue of the journal, Boston University ethicist George J. Annas compares genetic information to test results in a medical record, which are confidential. To accommodate researchers who wish to disguise pedigrees, Cyrillic, a pedigree software package available from Cherwell Scientific (Palo Alto, California), allows the user to remove, but save, personal family information that could lead to identification of an individual.

A generation ago, pedigrees and chromosome charts were often the only data accompanying genetics journal articles. Today, pedigrees share journal space with an ever-increasing number of gels, gene maps, and strings of A, T, C, and G. Pedigrees have adapted to the expanding nature of genetic research by including some other forms of data.

Many pedigrees now include vertical bars beneath the standard squares and circles, which indicate haplotypes. Haplotypes are themselves symbols for detectable DNA sequences (alleles) located near the gene of interest. A haplotype enables a researcher to clearly indicate a personís genotype (inherited allele combination), even if the phenotype (gene expression, such as a trait or disorder) is not obvious or has not yet developed. This symbol is particularly helpful, says Wallace, in instances of nonpenetrance, where an individualís case is so mild that he or she appears to be unaffected. Without haplotype bars, such a nonpenetrant person can cause researchers to make errors in establishing the mode of inheritance of a disease-causing gene. In practical terms, nonpenetrance can be interpreted as a false-negativeñthat is, a person may think that he or she cannot pass on a disease-causing gene, when he or she actually can.

In journals, pedigrees may indicate which persons had their DNA evaluated. A pedigree in the 27 May 1993 New England Journal of Medicine for a family with diabetes insipidus, for example, has a "P" next to symbols of relatives whose DNA was analyzed using the polymerase chain reaction (PCR) and an asterisk for individuals whose DNA was directly sequenced. In the pedigree standards adopted by the National Society of Genetic Counselors, clinical or test information is indicated by an "E" (for evaluated) beneath the circle or square symbol, and the information from the particular test is explained in an accompanying key. This symbol standardizes the nomenclature but allows for information addressing specific manifestations of a disorder.

For now, pedigrees seem to be expanding to include only a few additional bits of information per person. "Otherwise, you keep adding data and the pedigree expands [to be] so large that itís no longer useful as a quick reference," says Rodney Go, of the University of Alabama in Birmingham. He usually includes up to four lines of data beneath each pedigree symbol, which may include a description of the inherited trait, lab data or tests, or genetic markers.

Whether a genetic counselor uses a pad and pencil or a sophisticated, pedigree computer program depends largely on the setting. Counselors working where research is conducted, for example, at large medical centers, academic institutions, or specialized facilities such as the Mayo Clinic in Rochester, Minnesota, or the Memorial Sloan-Kettering Cancer Center in New York City, usually have access to computerized pedigrees. In contrast, a counselor working for a small, private medical practice or clinic may do just fine using the time-honored manual method.

Even without festooning a pedigree with haplotype bars, PCR notations, or genetic markers, using a computer can add both accuracy and speed. Attempting to sketch a pedigree of a large or complex family can require more erasing than drawing. Using a laptop computer with pedigree software, a genetic counselor can continue to make eye contact with clients as he or she inputs information.

"Picture a counseling session. The counselor writes information on a page, while listening, and later reconstructs what the patient said. Using a laptop at the session, she can get the patients involved, and get more information. She doesnít lose information or make errors when transcribing later, and the printer gives the patient a copy," says Steve Rankel, marketing manager for Cyrillic software at Cherwell Scientific.

Some pedigree software can tap into programs that calculate risks for specific disorders using such information as allele frequencies, mutation rates, and influences of other genes and environmental factors. The risk can be displayed under the appropriate symbol in the pedigree, says Rankel.

The genetics community is awaiting new computer programs to help with the pivotal pedigrees that both assist patients and launch research efforts. "As we go on, pedigree analysis will continue to be important. Even when the human genome project is completedñif it ever isñall of that work must, at some point, return to human pedigrees," says Keppler.

But Bennett adds, "Although pedigrees will continue to evolve, they can hardly be expected to one day represent the thousands of genes that are the genetic blueprints of a human. You have to remember what a pedigree is supposed to doñit is a quick and dirty shorthand. It is not meant to replace a clinical note or text of an article."

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