Medical Family History: Tools For Your Practice

Medical Family History: Tools For Your Practice
National Coalition for Health Professional Education in Genetics National Society of Genetic Counselors

After viewing this presentation, one should be able to:
Learning Objectives After viewing this presentation, one should be able to: List three benefits of taking family history in medical practice Create a pedigree using standard symbols Identify five genetic red flags Know how to locate family history tools Know how to locate a genetics professional Use the core competencies to interpret family histories in case examples

Family history may be the primary risk factor!
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. Knowledge of a patient’s family history has long been recognized as beneficial for diagnosis and treatment of relatively uncommon single-gene disorders, such as cystic fibrosis, fragile X syndrome, Huntington disease, familial hypercholesterolemia and other disorders inherited in classical Mendelian patterns. More recently, family history has been shown to be a major risk factor for more common chronic diseases such as cardiovascular disease, diabetes, several cancers, osteoporosis, and asthma. Therefore, including family history collection and interpretation in general health care is increasingly becoming standard of care. For example, in their Medical Genetics Core Educational Guidelines for Family Practice Residents, the American Academy of Family Physicians recommends that family physicians have the knowledge and skill to prepare and interpret a family history pedigree. The American College of Obstetricians and Gynecologists also lists health status of the patient's family as part of the screening that should take place during primary- and preventive- care assessments. These groups and others recognize that family history is an important screening tool and recommend that their members have the knowledge and skills to gather and interpret family history information. Family history may be the primary risk factor!

Why Family History? Family History Change Inform diagnosis management
Build rapport with patients Promote risk assessment and stratification Change management Collection of a patient’s family history, in conjunction with his or her traditional medical history information can do the following: Inform diagnosis: Whether a patient presents with a relatively uncommon single-gene disorder such as hemophilia, or a common complex condition such as cancer, knowledge of family history can promote more rapid diagnosis, streamlined testing, and better long-term management. Promote risk assessment: Medical family history information, in combination with other risk factors, can be used to estimate a patient’s risk of developing the same or similar condition as a relative, and to stratify that risk into higher or lower categories. Information such as the number of affected and unaffected relatives, age at onset of disease, severity of disease, and degree of relationship come into play in this assessment. This assessment can also determine if a patient is an appropriate candidate for genetic testing and can identify other relatives who might also be at high risk to develop a medical condition. Prevent, detect, and manage disease: Once a patient’s risk has been determined, the provider can suggest or advise appropriate interventions to improve the patient’s overall health and possibly prevent the onset of disease. In addition, if family history reveals that a patient is at increased risk, the provider can implement screening strategies to detect disease early, when it is most treatable. Some patients at increased risk may already have begun to manifest disease. For those individuals, family history assessment may help providers identify and manage the illness. The emphasis on disease prevention and management based on the family history may also motivate a change in behavior that forestall disease or reduce its adverse affects. Build rapport with patients: The act of taking a family history is an excellent opportunity to build a relationship with the patient. Through this interaction, the healthcare provider may also become aware of the patient’s motivations and concerns, as well as family dynamics. All such information can be beneficial as the provider helps the patient make health-related decisions.

COLLECTION INTERPRETATION INTERVENTION
The following core competencies are essential for collection and interpretation of a complete medical family history in pedigree format and the use of that information in patient management. The Family History Working Group from the National Coalition for Health Professional Education in Genetics (NCHPEG) initiated development of these core competencies. Working group members include physicians, nurses, social workers, genetic counselors and experts in genetics, education, patient advocacy, and disease prevention. This group recommends that all healthcare providers be familiar with the benefits of family history in healthcare and that healthcare providers involved in primary care and prevention, as well as healthcare specialists, become familiar with these core competencies. The core competencies are structured in a step-wise fashion, beginning with the collection of relevant family health information. Once collected, one can interpret the information by looking for patterns of inheritance and the presence of genetic red flags. This interpretation contributes to a general risk assessment, upon which individualized interventions are based. INTERVENTION

Collection 1) Recognize, understand, and use standard pedigree symbols
A 1993 survey of genetics practices showed wide variation in the pedigree symbols used by genetics professionals. A system of symbolization that is not uniform is of little utility. Through a peer-review process, the National Society of Genetic Counselors published recommendations for standardized pedigree nomenclature that is considered the international standard. The standard pedigree nomenclature is available from the NSGC website. (References: Bennett, R.L., Steinhaus, K.A., Uhrich, S.B., O'Sullivan, C.K., Resta, R.G., Lochner-Doyle, D., Markel, D.S., Vincent, V., & Hamanishi, J. (1995). Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors. Am J Hum Genet, 56(3), ) Bennett, et al. (1995). Recommendations for standardized human pedigree nomenclature. Am J Hum Genet, 56(3),

Identify the patient, or consultand, with an arrow
Collection 2) Produce at least a three-generation pedigree that includes: Identification of the patient Identify the patient, or consultand, with an arrow

(A consultand is often also a proband)
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) (References: Bennett, R.L., Steinhaus, K.A., Uhrich, S.B., O'Sullivan, C.K., Resta, R.G., Lochner-Doyle, D., Markel, D.S., Vincent, V., & Hamanishi, J. (1995). Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors. Am J Hum Genet, 56(3), )

Collection When the proband is not the consultand:
In this case, the patient’s sister is the first person to bring the family to medical attention. (References: Bennett, R.L., Steinhaus, K.A., Uhrich, S.B., O'Sullivan, C.K., Resta, R.G., Lochner-Doyle, D., Markel, D.S., Vincent, V., & Hamanishi, J. (1995). Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors. Am J Hum Genet, 56(3), )

Collection 2) Produce at least a three-generation pedigree that includes: Patient’s first-, second-, and third-degree relatives Information on maternal and paternal relatives Representation of “full” from “half” relationships example: children with same or different partner Affected and unaffected relatives

Collection 2) Produce at least a three-generation pedigree that includes: Identification of the historian, or person providing the information May be the patient or someone else, such as a parent Date of collection (or date of update), and name of collector (or updater) Legend or key, if symbols are used to designate disease

Degrees of Relationship
Collection Degrees of Relationship First-degree relatives: parents, siblings, children Second-degree relatives: half-siblings, aunts, uncles, grandparents, nieces & nephews Third-degree relatives: first cousins

Maternal and paternal relatives
Collection Maternal and paternal relatives Paternal Maternal

Collection 3) Elicit the following information for individuals represented in pedigree: Age, birth date, or year of birth Relevant health information Diagnosis, age at diagnosis Age at death, or years of birth/death Cause of death Ethnic background for each biological grandparent Adapted from: Bennett, R.L. (1999). The Practical Guide to the Genetic Family History. New York: Wiley-Liss.

Collection 3) Elicit the following information for individuals represented in pedigree: Infertility, or no children by choice Consanguinity Pregnancies Pregnancy complications (note gestational age) Miscarriages Preterm birth Stillbirths Preeclampsia Ectopic pregnancies Bleeding/clotting complications Pregnancy terminations Adapted from: Bennett, R.L. (1999). The Practical Guide to the Genetic Family History. New York: Wiley-Liss.

Collection Identification of patient
Patient’s first-, second-, and third-degree relatives Information on maternal and paternal relatives 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.

Collection Degree of relationship Age, birth date, or year of birth
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 yo yo 2 yo mo yo yo yo “hole in heart” 40 yo yo yo d. 54 yo yo yo 60 yo yo 63 yo accident depression lung cancer high cholesterol To the basic “skeleton” of the pedigree, we have added information about current ages of those who are still living, ages at death and causes of death for those who are deceased, and some basic relevant health information. Relevant information may change for each patient. As another slide will address, the information collected can be comprehensive (including general diagnoses or health status) or targeted for specific health conditions, such as cancer.

Collection 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 yo yo 2 yo mo yo yo yo “hole in heart” 40 yo yo yo d. 54 yo yo yo 60 yo yo yo accident depression, lung ca., 58 yo high cholesterol 42 yo Additional information has been added to this pedigree, specifically the ages at diagnosis. By designating certain diagnoses with symbols, one can easily differentiate affected individuals from unaffected individuals.

Collection 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 yo yo 2 yo mo yo yo yo “hole in heart” 40 yo yo yo d. 54 yo yo yo 60 yo yo yo accident depression, lung ca., 58 yo high cholesterol 42 yo by choice by choice Pregnancy histories may be added to a pedigree. This helps identify individuals with multiple miscarriages or pregnancy losses, histories of infertility, or those who have not chosen to have children for personal reasons.

Collection Ancestral background 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 yo yo 2 yo mo yo yo yo “hole in heart” 40 yo yo yo d. 54 yo yo yo 60 yo yo yo accident depression, lung ca., 58 yo high cholesterol 42 yo by choice by choice *no consanguinity reported* N. European German, English, American Indian The incidence of some disorders varies depending on the ancestry of the family. For example, sickle cell disease is most common in African Americans, while cystic fibrosis is most common in Caucasians of Northern European descent. Knowledge of a patient’s ancestry should not be the only information used in making a diagnosis, but it should be included in a comprehensive evaluation of family history. Knowledge of the ancestral background or geographic location of origin is more helpful than ethnicity because it is less subjective. Asking the question, “Do you know where your ancestors came from?” is one way to ask for this information. Consanguinity refers to a couple that is biologically related and has a child (or children) together. Marriage between cousins is a common practice in many parts of the world, although this practice is uncommon in the United States. In some cultures, an uncle-niece relationship is a preferred relationship. Children of consanguineous unions are at increased risk for autosomal recessive disorders or birth defects, because close relatives are more likely to share the same gene changes or mutations through a common ancestor than are unrelated individuals. Incest is a term that is usually reserved for the relationship between first-degree relatives, such as a parent and child, or two siblings. (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), )

Collection Legend or key, if symbols are used to designate disease
Date of collection (or update), name of collector (or updater) d. 70s d. mid 70s d. 55 yo d. late 60s “natural causes” dementia, mid 60s heart attack ca. (colon?), late 60s 35 yo yo yo 2 yo mo yo yo yo “hole in heart” 40 yo yo yo d. 54 yo yo yo 60 yo yo yo accident depression, lung ca., 58 yo high cholesterol 42 yo by choice by choice *no consanguinity reported* N. European German, English, American Indian Here is the finished pedigree, which includes the information collected at each step of the process. To the untrained eye, it may look cluttered. However, once you understand the symbols and notations, you can see that a pedigree is a great way to keep a lot of information organized and easily accessible. With family history displayed in this format, you can also easily visualize inheritance patterns or clustering that may make interpretation easier. Key: dementia cancer depression born with “hole in heart” Collected by: __________________ Collected on: __________________ Jane Doe August 20, 2006

Comprehensive vs. targeted family history
Collection Comprehensive vs. targeted family history Comprehensive General healthcare setting Elicit general health information about relatives Major medical concerns Chronic medical conditions Hospitalizations, surgeries Birth defects Mental retardation, learning disabilities, developmental delay Targeted Specialized clinical setting or evaluation for specific concerns Specific information about the condition of concern Comprehensive family history: In a general healthcare setting, providers should collect family histories by eliciting general health information about the relatives represented on a patient’s pedigree. Examples of conditions to ask about are: Major medical concerns Chronic medical conditions (something for which medication or therapy is required, for example) Hospitalizations or major surgeries Birth defects Mental retardation, learning disabilities, or developmental delay Targeted family history: A targeted family history is appropriate in a specialized clinical setting or when evaluating a patient for specific concerns. A targeted history includes information about health problems in a patient’s relatives that are related to the condition of concern. When evaluating a patient for a certain syndrome, for example, it would be most beneficial to ask about the presence in other family members of different features associated with that syndrome. A targeted family history would also be appropriate if the general family history reveals a possible inherited condition.

Additional Standard Pedigree Symbols
“4 females” “2 males” “3 females” N 3 4 2 These next pedigrees illustrate additional standard pedigree symbols. When representing multiple females or males, simply write the number of individuals within the sex symbol (such as with the “2 males” and “4 females”). If sex is unknown or a combination of males and females, use a diamond. Represent an unknown number of individuals or multiple individuals of both sexes with an “N” in a diamond. Two lines at the bottom of the line of descent is used when an individual has no children because of infertility. If known, note the cause of infertility at the bottom of the lines. No children-infertility “Unknown number or multiple children, males and females” Bennett, et al. (1995). Recommendations for standardized human pedigree nomenclature. Am J Hum Genet, 56(3),

Consanguinity: Relationships
First cousins First cousins once removed Second cousins Terms describing kinship are often confusing. These three pedigrees illustrate the relationship of first cousins, first cousins once removed, and second cousins— relationships that are commonly seen in consanguineous matings. Bennett, R.L. (1999). The Practical Guide to the Genetic Family History. New York: Wiley-Liss.

Consanguinity: An Example
1st cousins Note degree of relationship To illustrate a consanguineous relationship, use a double line between the two individuals. If known, note the degree of relation above the double lines. Bennett, et al. (1995). Recommendations for standardized human pedigree nomenclature. Am J Hum Genet, 56(3),

Affected Individuals Presymptomatic Individual Represent an affected individual by filling in his/her symbol. If someone is a presymptomatic carrier of a disease-causing mutation (verified by testing), a vertical line is put in his/her symbol. For example, let’s say that Huntington disease is inherited through this family. An individual may go forward with genetic testing before the onset of symptoms. If testing predicts the later onset of symptoms, that person would be represented with symbol for a presymptomatic carrier. Twins come out of the same individual line. To illustrate identical twins (monozygotic), connect the two individual lines with a horizontal line. Fraternal twins (dizygotic) do not have a horizontal line. Fraternal Twins (dizygotic) Identical Twins (monozygotic) Bennett, et al. (1995). Recommendations for standardized human pedigree nomenclature. Am J Hum Genet, 56(3),

Affected termination of pregnancy Termination of pregnancy P 2 12 wks 30 wks boy Miscarriage Affected miscarriage multiple congenital anomalies Pregnancies that end in spontaneous abortion (or miscarriage) are represented as a small triangle with their own individual line. This symbol is filled in if evaluation of the fetus is performed and a specific cause (a genetic condition, for example) of the miscarriage is identified. Elected terminations are represented with the same small triangle with a line through the symbol. Again, the symbol is colored in if the fetus is known to be affected by a specific condition. Pregnancies are represented by a diamond with a “P” in the symbol. If the sex is known, write it below the symbol. Note the gestational age if known. Unknown sex Known sex Pregnancy: Bennett, et al. (1995). Recommendations for standardized human pedigree nomenclature. Am J Hum Genet, 56(3),

Adoption into family Adoption out by relative An individual adopted into a family has a dashed individual line and the symbol (square or circle) is bracketed. As a general rule, non-biological children, as in the case of adoption, are represented with dashed lines. A child adopted out of a family is represented with a solid line and a bracketed symbol (square or circle). An individual adopted by a relative is connected to the adoptive parent(s) with a dashed line. Adoption out of family Bennett, et al. (1995). Recommendations for standardized human pedigree nomenclature. Am J Hum Genet, 56(3),

Egg donor/ gestational carrier D P Egg donor Sperm donor Pregnancies are represented by a diamond with a “P” in the symbol. If the sex is known, write it below the symbol. This symbol is placed directly below the individual carrying the pregnancy. Individuals participating in assisted reproductive technologies (such as sperm or egg donors) are represented in the pedigree with a “D” in their symbol. In this case, the donor provided an egg and is a surrogate or “gestational carrier.” Bennett, et al. (1995). Recommendations for standardized human pedigree nomenclature. Am J Hum Genet, 56(3),

Interpretation 1) Recognize basic inheritance patterns:
Single-gene disorders Autosomal Dominant Autosomal Recessive X-Linked Chromosomal disorders Extra/missing chromosomes Large-scale deletions or duplications Translocations Multifactorial disorders Multiple genetic and environmental factors Mitochondrial disorders Characterized by maternal transmission Usually neurological or neuromuscular symptoms

Single-gene Inheritance
Autosomal Dominant Characteristics of autosomal dominant inheritance: Affected individuals in every generation Every affected individual has an affected parent (with the exception of a new mutation) Any child of an affected individual has a 50% chance of inheriting the trait; unaffected family members do not pass it to their children Males and females equally likely to be affected (although there may be sex-limited expression, such as with ovarian cancer) Nussbaum, R.L., McInnes, R.R., & Willard, H.F. (2004). Thompson and Thompson, Genetics in Medicine: Sixth Edition, Revised Reprint. Philadelphia: Elsevier Saunders.

Autosomal Recessive Characteristics of autosomal recessive inheritance: Typically in one individual or individuals in same sibship/generation Males and females equally affected Parents of an affected individual are obligate carriers of a mutation AR conditions are seen in children of consanguineous couples The chance two carrier parents will have an (another) affected child is 1/4 (25%) Nussbaum, R.L., McInnes, R.R., & Willard, H.F. (2004). Thompson and Thompson, Genetics in Medicine: Sixth Edition, Revised Reprint. Philadelphia: Elsevier Saunders. Humans have two copies of nearly every gene in the genome. The term “carrier” refers to an individual who has one copy of a mutated (or disease-causing) gene and one copy of an unchanged or typical gene. In the case of autosomal recessive conditions, a carrier of a mutation is not clinically affected by the disorder. The status of having two different forms of one gene is referred to as “heterozygous.” The term “homozygous” refers to when both copies of the gene are identical. Carrier

X-Linked Characteristics of X-linked inheritance: (Dominant and recessive are used less frequently because carrier females of a “recessive” condition may show variable severity of the symptoms.) (Recessive) Males more often affected Heterozygous females are typically unaffected but may express trait with variable severity (depending on X inactivation) Mutations are transmitted from an affected male to all his daughters; mutations are transmitted through carrier females Carrier females have a 50% chance of passing the condition to their sons (Dominant) Affected males (with normal mates): no affected sons, all daughters are affected Affected (carrier) females: 50% chance of passing condition to each son or daughter Affected females about twice as common as affected males Nussbaum, R.L., McInnes, R.R., & Willard, H.F. (2004). Thompson and Thompson, Genetics in Medicine: Sixth Edition, Revised Reprint. Philadelphia: Elsevier Saunders.

Mitochondrial Inheritance
Characteristics of mitochondrial inheritance: Ovum (not sperm) is the source for a large proportion of mitochondria in a newly fertilized zygote A mother carrying a mitochondrial mutation will pass it on to ALL her offspring A father carrying a mitochondrial mutation does not pass it on to any of his offspring Nussbaum, R.L., McInnes, R.R., & Willard, H.F. (2004). Thompson and Thompson, Genetics in Medicine: Sixth Edition, Revised Reprint. Philadelphia: Elsevier Saunders.

Multifactorial Inheritance
Familial Clustering mood disorder alcoholism d. suicide anxiety/ depression depression Multifactorial conditions: disorders that result from complex interactions between multiple predisposing factors (ex: changes at multiple genetic loci) AND environmental exposures Inheritance does not follow that of typical single-gene conditions May be seen as familial clustering due to shared genes and environmental factors Risk of recurrence/occurrence is higher if more affected individuals Risks of disease to other relatives is based on empiric data This example shows inheritance of mental illness, a condition that is known to be caused by genes and environment. On the right, we see one individual in a family with depression. On the left, we see multiple individuals affected with a range of mental illness and a variety of manifestations. We can presume that this may be due to shared genetic predisposition and similar environmental triggers. Based on the number of affected individuals, we would expect that family members on the left are more likely to develop mental illness symptoms than family members on the right. Nussbaum, R.L., McInnes, R.R., & Willard, H.F. (2004). Thompson and Thompson, Genetics in Medicine: Sixth Edition, Revised Reprint. Philadelphia: Elsevier Saunders. ADHD

Chromosomal Translocation
CHD= Congenital heart defect CP= Cleft palate MR= Mental retardation SAB= Spontaneous abortion SS= Short stature = balanced translocation carrier SAB SAB SAB SAB SAB CHD CHD, CP CHD, CP MR, SS MR SAB SAB A family with recurrent miscarriages, and/or children with developmental delay, mental retardation, congenital anomalies, or abnormalities in growth is consistent with inheritance of a chromosomal translocation. The chance of having an affected child is usually based on observed frequencies and is much lower than the theoretical risk of passing on the unbalanced chromosome because some of the chromosomal combinations will be lethal.

Interpretation 2) Recognize Genetic Red Flags:
Do you think a condition present in a family may be genetic? Look for these clues: Family history of known or suspected genetic condition Multiple affected family members with same or related disorders Earlier age at onset of disease than expected Developmental delays or mental retardation Family history of known or suspected genetic disorder A patient may know the specific genetic disorder, or suspected diagnosis, that affects one or more relatives. When the patient knows of the disorder in vague or descriptive terms, one may be uncertain of the exact diagnosis. However, the accuracy of the information is supported when the patient knows the name of a specific diagnosis, especially if it is unusual. Awareness of a specific diagnosis facilitates immediate assessment and appropriate management if the patient is at-risk for this disorder. Multiple affected family members with same or related disorders “The presence of multiple affected family members could indicate a single-gene disorder that follows a Mendelian inheritance pattern: If each affected individual has an affected parent, the condition is likely autosomal dominant. Be aware that some conditions are expressed to varying degrees even within the same family. That means it is possible for a parent to be only mildly affected, but for his or her child to be severely affected. Keep in mind that individuals affected by the same condition may also exhibit different symptoms of the same disease. If neither of an affected individual’s parents is affected, the condition could be recessive. If only males seem to be affected, the condition could be X-linked. Multiple affected family members in a pedigree that does not follow a clear pattern such as dominant, recessive, or X-linked is also characteristic of complex traits, which are due to a combination of shared genetic and environmental factors among family members.”* Earlier age at onset of disease than expected “Throughout our daily lives, we are exposed to environmental influences that might cause damage to our genes, organs, or body systems. These exposures accumulate as we age, making it likely that a disorder that arises later in life is the result of a lifetime of environmental insults. Disorders that arise at an earlier age than expected are more likely caused by genetic factors.”* Developmental delays or mental retardation Environmental exposures can cause developmental delay and mental retardation. However, mental retardation and developmental delay can be due to chromosomal disorders, untreated or poorly managed inborn errors of metabolism, and some single gene disorders. As a result, the report of a relative (or several) fitting one of these descriptions should alert one to consider a possible genetic etiology. *Content courtesy of NCHPEG.

Interpretation 2) Recognize Genetic Red Flags (cont.):
Do you think a condition present in a family may be genetic? Look for these clues: Diagnosis in less-often-affected sex Multifocal or bilateral occurrence in paired organs One or more major malformations Disease in the absence of risk factors or after preventive measures Diagnosis in less-often-affected sex “Some disorders usually occur in females, and some usually occur in males. This is due to a variety of factors such as hormonal, developmental, and environmental differences. If a disorder occurs in the less-often-affected sex, however, it is likely that inherited genetic influences have superceded the other factors. For example, because male breast cancer is rare in the general population, when it occurs, it is highly suggestive of an underlying inherited etiology.”* Multifocal or bilateral occurrence in paired organs Environmental influences cause changes and damage to our bodies everyday. When they do, the damage is usually localized. This is because the chance of the change occurring in the first place is relatively small, and the chance that it would happen in two different locations independently is even smaller. On the other hand, when changes are due to genetic influences, we are more likely to see it in multiple locations. This is because our genes are in every cell of our body; a change that leads to damage is present throughout the body and does not need to happen multiple times in order to lead to damage in multiple locations. For example, retinoblastoma (malignant tumor of the retina) occurs sporadically unilaterally (only one eye). However, bilateral retinoblastoma is seen in individuals who inherit a mutation causing this cancer. One or more major malformation(s) Minor malformations are those differences that do not have substantial medical or cosmetic consequences, and may be associated with normal population variance. Before concluding that a minor malformation is significant, the parents should be examined. A slight physical change, such as differently shaped ears or syndactyly of the second and third toes, may be a familial trait. Major malformations, on the other hand, are birth defects of medical or cosmetic significance. These include heart defects, underdeveloped or absent organs, and cleft lip and/or palate. Some malformations can be isolated, arising because of a combination of environmental and genetic influences. However, a genetic syndrome is suspected when one (or more) major malformation is present, multiple minor malformations are present, or a combination of the two. In these cases, an underlying genetic etiology explains severe or multiple malformations better than them occurring by chance.** Disease in the absence of risk factors or after preventive measures We can change our diet, amount of exercise, level of stress, and other environmental factors in order to avoid the onset of disease or illness. One thing we cannot change is our genetic make-up. For someone who follows a low risk lifestyle and/or performs radical preventative measures and still develops symptoms, it would be reasonable to infer this person has a strong genetic predisposition to disease. Despite controlling for environmental risk factors, one’s genetic make-up may still lead to the onset of disease. * Content courtesy of NCHPEG ** Adapted from Bennett, R.L. (1999). The Practical Guide to the Genetic Family History. New York: Wiley-Liss.

Interpretation 2) Recognize Genetic Red Flags (cont.):
Do you think a condition present in a family may be genetic? Look for these clues: Abnormalities in growth (growth retardation, asymmetric growth, excessive growth Recurrent pregnancy losses (2+) Consanguinity (blood relationship of parents) Ethnic predisposition to certain genetic disorders Abnormalities in growth (growth retardation, asymmetric growth, excessive growth) Though not the only causes of abnormalities in growth, genetic conditions should be considered when evaluating an individual for prenatal or postnatal growth changes or deficiencies, especially in the absence of risk factors such as malnutrition. Many genetic disorders and syndromes are known to cause growth retardation, asymmetric growth, and/or excessive growth. In fact, the specific pattern of abnormal growth may be crucial in making a diagnosis. Recurrent pregnancy losses (2+) “Spontaneous miscarriage can occur in the first or second trimester when an isolated change to the chromosomes or genes has occurred in the fetus. However, if one of the parents carries a structural or numerical change in their chromosomes or other gene changes, it could lead to more frequent pregnancy losses. The presence of multiple spontaneous miscarriages in an individual, or several related individuals, indicates an underlying genetic modification or large-scale change. This can result in a spectrum of outcomes ranging from spontaneous miscarriage on one extreme to genetic disorders in a child on the other extreme.”* Consanguinity (blood relationship of parents) “Consanguinity is a relationship by blood or a common ancestor. Children from a consanguineous couple (related as first cousins or closer) have an increased risk of being affected by autosomal recessive conditions. This is because two parents who are related are more likely to share the same genes than two unrelated individuals, so each parent may pass the same disease-causing gene to his or her child. In autosomal recessive disorders, the parents who carry one copy of the disease gene are not affected, but a person who inherits two copies of the disease gene is affected. Children of consanguineous couples are also at an increased risk for inheriting complex conditions. “As the degree of relationship between two individuals decreases (for example, second cousins vs. first cousins), the likelihood of their children being affected by an autosomal recessive condition also decreases.”* Ethnic predisposition to certain genetic disorders “The incidence of some disorders varies depending on the ancestry of the family. For example, sickle cell disease is most common in African Americans, while cystic fibrosis is most common in Caucasians of Northern European descent. Knowledge of a patient’s ancestry should not be the only information used in making a diagnosis, but it should be included in a comprehensive evaluation of family history. Note that knowledge of the region of geographic origin is more helpful than ethnicity, because ethnicity is much more subjective.”* * Content courtesy of NCHPEG

Interpretation Pedigrees
Pedigree: uses standard symbols and terminology to represent a large amount of information in a diagram Preferred method of organizing and displaying family history Benefits: organize a great deal of information visualize inheritance patterns and familial clustering There are multiple ways to collect key information about the medical history of a patient and his or her family members, and, once collected, there are different ways to organize and display that information. The preferred method of organizing and displaying family medical information is the pedigree, which uses standard symbols and terminology to represent a large amount of information in a diagram. Charts or lists can include all necessary information, but, unlike pedigrees, may make it difficult to visualize inheritance patterns and familial clustering.

Interpretation Pedigrees or Checklists?
Crucial element: THE INFORMATION! The method used must: be reasonably accurate be updated easily allow for pattern detection and interpretation provide clear communication between healthcare providers However, the critical element of the family history is the information, not the format. The method of collection used must: be reasonably accurate, be updated easily, allow for pattern detection and interpretation, and provide for clear communication between healthcare providers. Genetics and Common Disorders: Implications for Primary Care and Public Health Providers. National Coalition of Health Providers Education in Genetics. April 2005.

Educational opportunities
Interpretation Educational opportunities Eliciting and summarizing family history information can: help the patient understand the condition in question clarify patient misconceptions help the patient recognize the inheritance pattern of the disorder demonstrate variation in disease expression (such as different ages at onset) provide a visual reminder of who in the family is at risk for the condition emphasize the need to obtain medical documentation on affected family members Collection and interpretation of a patient’s family history provide excellent teaching opportunities for the patient and healthcare provider. Eliciting and summarizing family history information can: Bennett, R.L. (1999). The Practical Guide to the Genetic Family History. New York: Wiley-Liss.

Cautions and Constraints
Interpretation Cautions and Constraints Missing information vs. unaffected relatives Reliability of information Non-traditional families Unknown paternity Adoption Cultural definitions of family Cultural biases Consanguinity Confidentiality As a classroom exercise, brainstorm ideas demonstrating how instances of these cautions and constraints can interfere with interpretation of a patient’s family history and potential health risks. 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),

Intervention 1) Identify where more specific information is needed and obtain records 2) Assess general risks 3) Know when to refer to genetics professionals 4) Encourage the patient to talk to other family members Identify where more specific information is needed and obtain records Risk assessment is difficult if specific diagnoses or test results are not known. Additional information may be needed to rule out some possibilities. It might be necessary to obtain other medical records (after obtaining permission for release) before further steps are taken with a patient. Assess general risks: see next slide Know when to refer to genetics professionals Primary care providers recognize and treat a wide range of general health problems. Although general familiarity with genetics is necessary for optimum patient care, it is not feasible for non-geneticists to be experts on relatively uncommon single-gene disorders and all genetic contributions to disease. The goals for those working in primary care are to 1) recognize when genetics may be contributing to disease in a family, 2) take appropriate measures for management of disease in light of that information, and 3) know when and how to refer a patient and/or other family members to genetics or other specialists when the situation requires. Encourage the patient to talk to other family members A patient may have limited knowledge of the medical histories of family members. In such cases, encouraging the patient to talk with relatives to gather additional information can improve the reliability of risk assessment. In addition, if the provider suspects an inherited disorder in the family, the patient can communicate that suspicion to relatives and encourage them to seek medical consultation for personal risk assessment. Update pedigree at subsequent visits An advantage of organizing family history information in pedigree form is that one can update the information easily during subsequent patient visits. Providers can add recent births, deaths, and new diagnoses to keep a patient’s family history up-to-date. 5) Update pedigree at subsequent visits

Risk Classification Standard public health prevention recommendations
Personalized prevention recommendations Personalized prevention recommendations and referral for genetic evaluation Average Moderate High Family History Tool Standard public health prevention recommendations Assess general risks When taken with care, a patient’s family history can provide information needed to determine a general risk that he or she (or other family members) may develop any number of disorders. A general risk assessment will assign a patient to an average, moderate, or high-risk group, and each classification implies different recommendations for health management. For example, management of “high risk” patients could include increased surveillance or prevention efforts. Other at-risk family members may also be candidates for increased prevention, surveillance, and changes in management. Diagram adapted from: Yoon, P.W., Scheuner, M.T., & Khoury, M.J. (2003). Research priorities for evaluating family history in the prevention of common chronic diseases. Am J Prev Med, 24(2),

Follow-up with patients and other providers
Intervention Follow-up with patients and other providers Other providers Follow-up with patients and other providers Patient management requires consistent follow-up and communication with the patient and with other providers involved in the patient’s care. That is especially true when referring a patient to, or accepting the referral from, another provider. In such situations, the providers should discuss the indications for referral. Regular follow-up with patients is also important. It is necessary, for example, to follow-up with patients to communicate test results and discuss the implications. Follow-up on treatment plans or strategies for prevention also are important for optimal care. Patient(s)

Available Family History Tools
Surgeon General’s Family History Initiative: “My Family Health Portrait” familyhistory.hhs.gov

“Family History: Resources and Tools” (CDC)

AMA’s Genetics & Molecular Medicine: Family History

“Your Family History- Your Future” (NSGC, Genetic Alliance, ASHG)

How to Find a Genetics Professional
1. National Society of Genetic Counselors Find a counselor according to location, institution, or area of specialization To locate a genetics professional in your area, visit the following organizations: National Society of Genetic Counselors (NSGC), (Click on “Find a Counselor” under Quick Links) GeneClinics, (Click on “Clinic Directory” in center of screen) American Society of Human Genetics (ASHG), (Click on “Find a Member” in top left of screen)

2. GeneClinics To locate a genetics professional in your area, visit the following organizations: National Society of Genetic Counselors (NSGC), (Click on “Find a Counselor” under Quick Links) GeneClinics, (Click on “Clinic Directory” in center of screen) American Society of Human Genetics (ASHG), (Click on “Find a Member” in top left of screen) A voluntary listing of US and international genetics clinics providing genetic evaluation and genetic counseling

3. American Society of Human Genetics To locate a genetics professional in your area, visit the following organizations: National Society of Genetic Counselors (NSGC), (Click on “Find a Counselor” under Quick Links) GeneClinics, (Click on “Clinic Directory” in center of screen) American Society of Human Genetics (ASHG), (Click on “Find a Member” in top left of screen)

Case Examples

Saundra’s Family A new patient, Saundra, states that many individuals in her family have had cancer, especially colon cancer. She is certain that she is destined to develop cancer in the near future.

Saundra’s Family How can taking Saundra’s family history help to assess her risk to develop colon cancer? Identify specific relatives with colon or other cancers 2) Identify the ages at the diagnosis of cancer 3) Identify family members who have not had cancer 4) Identify the side (or sides) of the family on which cancer is present

How did you assess her risk?
Saundra’s Family d. 72 yo d. 68 yo d. 59 yo d. 70 yo dx 72 yo dx 69 yo 68 yo yo d. 66 yo yo 78 yo yo yo dx 65 yo dx 59 yo dx 52 yo 45 yo yo yo yo yo yo yo yo yo yo yo Colon cancer Lung cancer Melanoma In taking Saundra’s family history, you find out the following information: She has an older brother who is 52 years old and an older sister who is 49. Her mother is 76 years old and has not had any cancers. Her mother’s older brother (78 years old) was diagnosed with colon cancer at 59. Her younger sister (71 years old) was diagnosed with melanoma at 52 years old. She has another younger sister (70 years old) who has not had any cancer. Saundra’s maternal aunts and uncle have children, but none has been diagnosed with cancer. Saundra’s maternal grandmother died at 70 years of age from colon cancer diagnosed at 69 years of age, and her grandfather died at 59 from a heart attack. Saundra’s father was diagnosed with colon cancer at 65 and died a year later. He has one brother who is 68 and one sister who is 60. Neither of his siblings has had cancer. Saundra’s paternal aunt and uncle have children, but none has been diagnosed with cancer. Saundra’s paternal grandfather died from lung cancer at age 72; she reports he smoked for many years. Her paternal grandmother died at age 68, “in her sleep.” It is true that many of Saundra’s relatives have been diagnosed with cancer; however, the diagnoses are less consistent with a hereditary form of cancer and more consistent with cancers caused by environmental exposures. Colon cancer is relatively common in individuals over the age of 60. The individuals diagnosed with cancer in Saundra’s family were either more than 60 years old or close to it. Also, while two individuals with colon cancer are in the same side of the family, the other cancer is from a different side of the family. It is reasonable to consider Saundra at low risk (approximately general population risk) to develop colon cancer based on her family history. Standard colon-cancer surveillance would be appropriate for Saundra. Do you think that Saundra has a low, moderate, or high risk of developing colon cancer based on her family history? How did you assess her risk?

How did you assess her risk?
Saundra’s Family Saundra’s Family d. 72 yo d. 54 yo d. 59 yo d. 70 yo dx 72 yo dx 52 yo dx 69 yo 68 yo yo d. 56 yo yo 78 yo yo yo dx 59 yo dx 53 yo dx 50 yo dx 59 yo dx 52 yo 45 yo yo yo yo yo yo yo yo yo yo yo dx 49 yo Let’s consider a different family history. Saundra’s maternal family history has not changed. In this case, in a routine colonoscopy at age 49, Saundra’s older brother was found to have precancerous colon polyps, which were removed. He made sure to have a colonoscopy before age 50 because their father had been diagnosed with colon cancer at age 50 years and died at 56, and their paternal grandmother had been diagnosed with colon cancer at age 52 and died two years later. Saundra’s paternal uncle was diagnosed with colon cancer at 59 years of age. Her paternal aunt was also found to have precancerous colon polyps during a colonoscopy at age 53. Again, Saundra’s paternal grandfather died from lung cancer at age 72; she reports he smoked for many years. Her paternal grandmother died at age 68 “in her sleep.” This family history significantly changes Saundra’s risk to develop colon cancer. Her father’s age at diagnosis is young compared to the general population, and she has two second-degree relatives diagnosed with colon cancer relatively young. As well, her brother and paternal aunt were found to have precancerous colon polyps also at young ages. While Saundra’s maternal side of the family has not changed, her paternal side of the family is more consistent with a hereditary colon cancer syndrome because there are multiple people with colon cancer in multiple generations and each was diagnosed at a young age. It is reasonable to consider Saundra at high risk to develop colon cancer based on her family history. Because of this, Saundra should increase her colon-cancer surveillance over that of the general population. She may even consider genetic counseling and a discussion about genetic testing. Do you think that Saundra has a low, moderate, or high risk of developing colon cancer based on her family history? Colon cancer Lung cancer Melanoma Colon polyps How did you assess her risk?

Saundra’s Family Factors decreasing risk of genetic basis to condition in first scenario Cancers common in general population Affected relatives are older at diagnosis Cancer on both sides of family Factors increasing risk of genetic basis to condition in second scenario Affected relatives are relatively young at diagnosis Multiple affected relatives concentrated on same side of family It is true that many of Saundra’s relatives have been diagnosed with cancer; however, the diagnoses are less consistent with a hereditary form of cancer and more consistent with cancers caused by environmental exposures. Colon cancer is relatively common in individuals over the age of 60. The individuals diagnosed with cancer in Saundra’s family were either more than 60 years old or close to it. Also, while two individuals with colon cancer are in the same side of the family, the other cancer is from a different side of the family. It is reasonable to consider Saundra at low risk (approximately general population risk) to develop colon cancer based on her family history. Standard colon-cancer surveillance would be appropriate for Saundra. This family history significantly changes Saundra’s risk to develop colon cancer. Her father’s age at diagnosis is young compared to the general population, and she has two second-degree relatives diagnosed with colon cancer relatively young. As well, her brother and paternal aunt were found to have precancerous colon polyps also at young ages. While Saundra’s maternal side of the family has not changed, her paternal side of the family is more consistent with a hereditary colon cancer syndrome because there are multiple people with colon cancer in multiple generations and each was diagnosed at a young age. It is reasonable to consider Saundra at high risk to develop colon cancer based on her family history. Because of this, Saundra should increase her colon-cancer surveillance over that of the general population. She may even consider genetic counseling and a discussion about genetic testing.

Saundra’s Family Utility of family history tools: Collection
Focus on diagnoses and ages, as well as affected and unaffected individuals Interpretation Consider red flags: multiple affected family members, early age at onset Implementation Assessment of risk alters recommended surveillance

Toby’s Family During a routine visit, Toby mentions that he is extremely conscious of his physical health because he does not want to get heart disease like the other members of his family.

Toby’s Family How can taking Toby’s family history help to assess his risk to develop heart disease? Identify specific relatives with heart disease and associated complications Identify the ages at onset of disease 3) Identify the presence or absence of risk factors in relatives with heart disease

How did you assess his risk?
Toby’s Family d d d. 52 yo yo OB, SM Alz car accident A&W HA, 64 yo A&W: alive and well Alz: Alzheimer's HA: heart attack HBP: high blood pressure HC: high cholesterol OB: obese RegEx: regular exercise SM: smoker T2D: type 2 diabetes 64 yo yo yo yo yo OB, HBP T2D, HC OB, T2D HBP, HC HA , 55 yo 40 yo yo yo yo yo yo yo OB reg.ex. HBP C, BP: WNL Toby is able to share a bit about his family history. He is 27 years old and is physically active and in good shape. His cholesterol and blood pressure are within normal limits. He has a sister who is 34 years old. Their father is 58 years old; he is obese, has high blood pressure, high cholesterol, and has developed type 2 diabetes. He had a heart attack at 55. Toby’s paternal uncle is 61 years old, has high cholesterol, and has also developed type 2 diabetes. Toby’s paternal aunt is 64-years-old, is obese and has high blood pressure. Similarly, her 40-year-old son is obese and has high blood pressure. Toby’s paternal grandfather was obese and was a smoker for most of his life. He had a heart attack at 64 and died at age 68. Additional family history is as noted. Risk factors for heart disease include obesity (being overweight), smoking, and sex: males are more likely to have heart disease. It appears that Toby’s relatives with heart disease also have one or more of these risk factors. It is likely that if Toby stays healthy and avoids these risk factors, his risk to develop heart disease is low. Do you think that Toby has a low, moderate, or high risk of developing heart disease based on his family history? How did you assess his risk?

How did you assess his risk?
Toby’s Family d d d. 52 yo yo HA, 55 yo Alz car accident A&W A&W: alive and well Alz: Alzheimer's HA: heart attack HBP: high blood pressure HC: high cholesterol OB: obese RegEx: regular exercise SM: smoker d. 48 yo yo d. 50 yo yo yo reg.ex. HBP, HC HC HC HA , 49 yo HA, 48 yo 40 yo yo yo yo yo yo yo HBP, HC reg.ex. C, BP: WNL Here’s an alternative family history. In this case, Toby’s medical presentation and maternal family history are the same. However, his father died at 50 after having had a heart attack at age 49. Toby’s father had high cholesterol his adult life despite being physically active and average weight. Toby’s paternal uncle is 61 years old, has high cholesterol and high blood pressure. Despite engaging in regular exercise, Toby’s paternal aunt died at 48 from a heart attack. She also had high cholesterol. Her 40-year-old son also has high cholesterol and high blood pressure. Toby reported that his paternal grandfather died at 55 from a heart attack. Additional family history is as noted. This alternative family history changes Toby’s risk to develop heart disease. That is because, in this case, the heart disease present in Toby’s family members developed at a relatively young age and in the absence of risk factors. Although Toby is still healthy, it is reasonable to consider him to be at an increased risk to develop heart disease because of his family history. While heart disease is a condition commonly seen in the general population and is generally due to external factors, the family history represented here suggests a genetic component to the diagnoses of high cholesterol and heart attacks at a young age in the absence of external risk factors. Knowledge of Toby’s modified risk has implications for management of his health, including genetic testing. Do you think that Toby has a low, moderate, or high risk of developing heart disease based on his family history? How did you assess his risk?

Toby’s Family Factors decreasing risk of genetic basis to condition in first scenario Affected family members have multiple risk factors, some of which are environmental Affected relatives are older at diagnosis Factors increasing risk of genetic basis to condition in second scenario Affected relatives are relatively young at diagnosis Disease in the absence of risk factors Risk factors for heart disease include obesity (being overweight), smoking, and sex: males are more likely to have heart disease. It appears that Toby’s relatives with heart disease also have one or more of these risk factors. It is likely that if Toby stays healthy and avoids these risk factors, his risk to develop heart disease is low. This alternative family history changes Toby’s risk to develop heart disease. That is because, in this case, the heart disease present in Toby’s family members developed at a relatively young age and in the absence of risk factors. Although Toby is still healthy, it is reasonable to consider him to be at an increased risk to develop heart disease because of his family history. While heart disease is a condition commonly seen in the general population and is generally due to external factors, the family history represented here suggests a genetic component to the diagnoses of high cholesterol and heart attacks at a young age in the absence of external risk factors. Knowledge of Toby’s modified risk has implications for management of his health, including genetic testing.

Toby’s Family Utility of family history tools: Collection
Focus on diagnoses and ages at onset; also consider presence or absence of risk factors Interpretation Consider red flags: multiple affected family members, early age at onset, disease in the absence of risk factors and in the less-often-affected sex Implementation Assessment of risk alters recommended testing and health management

Baby Maria’s Family Maria (one month old) was born with a cleft lip and palate (CL/P). CL/P is commonly isolated, but can also be a part of a number of different inherited syndromes. Isolated Cleft lip and/or palate occurs in 1 out of every 1000 births (0.1%). Knowing the details of all of the genetic syndromes associated with cleft lip and/or palate would be too overwhelming. It is important, however, to recognize the presence of multiple features that may be suggestive of a syndrome, and then investigate further if necessary. A “targeted” family history may be taken by asking about features commonly seen with CL/P in different syndromes (such as heart defects or other birth defects, or learning difficulties). By taking Maria’s family history, we can look for the “genetic red flags” that might lead us to suspect that there is an underlying inherited condition that caused her cleft lip and palate. The recurrence risks of CL/P in future children are different if it isolated or syndromic.

Baby Maria’s Family How can taking Maria’s family history help assess whether her CL/P is isolated or syndromic? Identify whether features are present in other family members that are suggestive of a syndrome If features are present, identify an inheritance pattern Isolated Cleft lip and/or palate occurs in 1 out of every 1000 births (0.1%). Knowing the details of all of the genetic syndromes associated with cleft lip and/or palate would be too overwhelming. It is important, however, to recognize the presence of multiple features that may be suggestive of a syndrome, and then investigate further if necessary. A “targeted” family history may be taken by asking about features commonly seen with CL/P in different syndromes (such as heart defects or other birth defects, or learning difficulties). By taking Maria’s family history, we can look for the “genetic red flags” that might lead us to suspect that there is an underlying inherited condition that caused her cleft lip and palate. The recurrence risks of CL/P in future children are different if it isolated or syndromic. Why is this helpful? Better management of associated health problems Determine recurrence risk for future children

How did you assess this chance?
Baby Maria’s Family 5 yo yo yo mo yo yo yo asthma CL/P 31 yo yo yo yo yo anxiety high cholesterol 62 yo yo 60 yo yo heart attack, 59 yo “liver disease” Cleft lip and palate Key: You are able to learn more about Maria’s family history through her parents. They report that they have another daughter, who is 3 years old. She has had no medical complications and did not have any birth defects. Neither Maria’s father (32 years old) or her mother (29 years old) has any medical concerns. Maria’s father has one sister (31 years old), who is reportedly a very anxious person. She has two sons who are 5 and 2. Her older son has asthma, but there are no other reported health concerns. Maria’s paternal grandfather had a heart attack at age 59, but is currently 62 and is reported to be doing well. Her paternal grandmother is 57 years old and is reported to be healthy. Maria’s mother has two siblings: a 37-year-old brother (who has high cholesterol) and a 33-year-old sister. Her brother has a 13-year-old daughter who is doing fine, and her sister has two sons (8 and 6), who also have no reported health concerns. Maria’s maternal grandfather is 60 years old and is generally healthy, and her maternal grandmother is 59 years old and is reported to have “liver disease,” but additional information is limited. Based on this history, it is likely that Maria’s CL/P is isolated. (Again, isolated cleft lip and/or palate occurs in 1 out of every 1000 births, or 0.1% of live births.) Maria’s family history shows the presence of some health conditions, but they are things that are common in the general population. In addition, they are present on both maternal and paternal sides of her family, with no clear inheritance pattern or familial clustering. Do you think that there is a low, moderate, or high chance that Maria’s cleft lip and palate is due to an inherited condition? How did you assess this chance?

Baby Maria’s Family Isolated Cleft Lip and/or Palate:
1 in 1000 births (0.1%) Recurrence risks Maria’s sibling: 2%-8% Maria’s child: 4%-6% Isolated Cleft lip and/or palate occurs in 1 out of every 1000 births (0.1%). Determining whether Maria’s cleft lip and palate is inherited is crucial for informing her parents of the chance that future children will also be affected. If Maria’s parents have another child, the chance that Maria’s younger sibling will have a cleft lip and palate is 2%-8%. If Maria has children, there is a 4%-6% chance that each child will also have cleft lip and palate.

Baby Maria’s Family 5 yo yo yo mo yo yo yo asthma CL/P heart defect nasal speech 31 yo yo yo yo yo anxiety LD hearing loss “nasal speech” 62 yo yo 60 yo yo heart attack, 59 yo CP, LD Cleft lip and/or palate LD= Learning difficulties Nasal speech Heart defect Hearing loss Key: Suppose you get a different family history. In this case, Maria’s paternal family information has not changed. However, you identify some additional features on her maternal side. Maria’s mother reports that school was very difficult for her, that she didn’t understand the material as quickly as her classmates, and that kids used to tease her for talking funny. In speaking with her, you notice a “hypernasal” quality to her speech. She reports that her sister has had moderate hearing loss since she was born. While neither of her nephews has hearing loss, her 8-year-old nephew was born with a heart defect and has been in therapy for a while because of his nasal speech. Maria’s maternal grandmother was born with a cleft palate, and dropped out of school when she was younger because it was difficult for her to keep up with the material. This new information starts to paint a picture of an inherited condition. Although we don’t see all the same findings in the affected individuals, we see a clustering of potentially related features. The red flags that should come to mind are: multiple affected family members, early age at onset (hearing loss as a child), developmental delays (learning difficulties), and one or more major malformation. The pattern of inheritance appears to be autosomal dominant. The features that Maria’s mother reported in her family members are consistent with a diagnosis of 22q deletion syndrome. This condition, which is inherited in an autosomal dominant manner, is due to a sub-microscopic deletion of a region of DNA on chromosome 22. (22q deletion syndrome is actually a general term referring to a handful of separate but similar conditions due to deletions on chromosome 22.) The main features of this condition include: congenital heart defects, cleft palate (and cleft lip), learning difficulties, immune deficiency, hypocalcemia, and characteristic facial features. A diagnosis of 22q deletion syndrome provides important recurrence risk information. Because it is autosomal dominant, there is a 50% chance that Maria’s next sibling will have the same condition. There is also a 50% chance that each of Maria’s children will have 22q deletion syndrome. A diagnosis also has important implications for the health management of all the affected individuals, which is important because there are other health issues that require monitoring. Do you think that there is a low, moderate, or high chance that Maria’s cleft lip and palate is due to an inherited condition? How did you assess this chance?

Baby Maria’s Family 22q Deletion syndrome:
Deletion of submicroscopic deletion of ch. 22q Inheritance: autosomal dominant Recurrence risks: Maria’s sibling: 50% Maria’s child: 50% Primary features: Congenital heart defects Immune deficiency Cleft lip and palate Hypocalcemia Learning difficulties Characteristic facies The features that Maria’s mother reported in her family members are consistent with a diagnosis of 22q deletion syndrome. This condition, which is inherited in an autosomal dominant manner, is due to a sub-microscopic deletion of a region of DNA on chromosome 22. (22q deletion syndrome is actually a general term referring to a handful of separate but similar conditions due to deletions on chromosome 22.) The main features of this condition include: congenital heart defects, cleft palate (and cleft lip), learning difficulties, immune deficiency, hypocalcemia, and characteristic facial features. A diagnosis of 22q deletion syndrome provides important recurrence risk information. Because it is autosomal dominant, there is a 50% chance that Maria’s next sibling will have the same condition. There is also a 50% chance that each of Maria’s children will have 22q deletion syndrome. A diagnosis also has important implications for the health management of all the affected individuals, which is important because there are other health issues that require monitoring.

Baby Maria’s Family Factors decreasing risk of inherited syndrome in first scenario Presence of non-specific health conditions common in the general population Features on both maternal and paternal sides No clear inheritance pattern or family clustering Factors increasing risk of inherited syndrome in second scenario Clustering of potentially related features Several genetic red flags are present Clear autosomal dominant inheritance Maria’s family history shows the presence of some health conditions, but they are things that are common in the general population. In addition, they are present on both maternal and paternal sides of her family, with no clear inheritance pattern or familial clustering. This new information starts to paint a picture of an inherited condition. Although we don’t see all the same findings in the affected individuals, we see a clustering of potentially related features. The red flags that should come to mind are: multiple affected family members, early age at onset (hearing loss as a child), developmental delays (learning difficulties), and one or more major malformation. The pattern of inheritance appears to be autosomal dominant.

Baby Maria’s Family Utility of family history tools: Collection
Specifically ask about features that are often seen in syndromes associated with CL/P Interpretation Consider red flags: multiple affected family members, early age at onset, developmental delays, one or more major malformation Implementation Presence of a syndrome can alter recurrence risks and health management for the patient and family members

Anne and Geoff Anne and Geoff want to start a family. Following ACOG guidelines, Anne’s physician makes cystic fibrosis (CF) carrier screening available to all her patients, and recommends screening to her patients who are Northern European (including Ashkenazi Jewish) or who have a family history of CF. American College of Obstetricians and Gynecologists, American College of Medical Genetics. Preconception and prenatal carrier screening for cystic fibrosis: clinical and laboratory guidelines. Washington, DC: ACOG; Bethesda (MD): ACMG; 2001. American College of Obstetricians and Gynecologists, American College of Medical Genetics. Preconception and prenatal carrier screening for cystic fibrosis: clinical and laboratory guidelines. Washington, DC: ACOG; Bethesda (MD): ACMG; 2001.

Anne and Geoff How can Anne and Geoff’s family histories help the physician decide whether to recommend CF carrier testing or simply make it available to Anne and Geoff? Identify whether CF is present in the family Determine whether Anne or Geoff are of ancestries for which CF carrier screening is recommended In addition to providing the physician with important general information about Anne and Geoff’s future pregnancy, the family history can determine whether or not Anne and Geoff are good candidates for carrier testing. Carrier testing usually begins with the mother (in this case, Anne), and if she is found to be a carrier then her partner is tested. For autosomal recessive conditions like CF, if the mother is not a carrier, knowing her partner’s status does not change the risk assessment for their pregnancy. The results of the CF carrier screen can give Anne and Geoff a more accurate estimate of the chance that they could have a child with CF. 3) Identify other family members who may consider carrier testing

Anne and Geoff Cystic Fibrosis: Multisystem disease
Pulmonary: accumulation of mucus Digestive: malnutrition and constipation Reproductive: bilateral absence of vas deferens (infertility) Inheritance: autosomal recessive Average life span: young adulthood Cystic fibrosis is a multisystem disease that affects pulmonary, digestive, and reproductive systems. Individuals with CF accumulate mucus in their lungs, making it difficult to breath and increasing the frequency of pulmonary infections. The digestive tracts in individuals with CF do not absorb food and nutrients efficiently, leading to malnutrition and constipation. Males with CF have absence of the vas deferens, which leads to infertility. Treatment and management of the condition has improved, increasing the average lifespan of an individual with CF from childhood to young adulthood. It is an autosomal recessive condition, so both parents must be carriers of a mutation in the CF gene to have a child with CF (carriers are not symptomatic). If both parents are carriers, there is a 25% (or 1 in 4) chance that each of their children will have CF. There is an increased frequency of CF in those of Northern European and Ashkenazi Jewish descent.

Anne and Geoff Northern European, Russian African American, American Indian 56 yo yo yo yo high BP (early 40s) diabetes blood clot- leg (54 yo) (mid 40’s) 34 yo yo yo yo yo yo irritable bowel migraines mitral valve syn.(31 yo) (late teens) prolapse (mid 20’s) 7 yo yo yo yo yo yo born at 37 wks Anne offers some information about her family history, and Geoff, who has accompanied her to the appointment, tells you about his family. Anne is 25 years old. She has a 32-year-old sister with one healthy son. Her sister was diagnosed with mitral valve prolapse in her mid-20s, but it hasn’t caused her any problems. Anne’s older brother, who is 29 years old, has 2-year-old twins- a boy and a girl. Other than being delivered a few weeks prematurely, they have had no health problems. Anne’s father, who is 59 years old, has diabetes, and her mother, who is 57 years old, had a blood clot in her leg about 3 years ago. Anne’s family is mostly African American, with a bit of American Indian. Geoff says that he’s been experiencing migraines since his late teens, but has no other health concerns. He has two older sisters. One is 34 years old. She was diagnosed with irritable bowel syndrome at 31, but has been able to manage it very well. She has a 7-year-old son and a 4-year-old daughter, neither of whom has health problems. His other sister is 30 years old. She doesn’t have any health problems and neither does her 3-year-old daughter. Geoff’s mom, who is now 57 years old, was diagnosed with high blood pressure in her early 40’s. His dad, who is 56, has no major health concerns. Geoff reports that his ancestors were mostly from Northern Europe and maybe Russia. Based on this family history, it seems that Anne is at a low risk to be a CF carrier because of her ancestry. Because Geoff is mostly Northern European, there is a 1 in 25 chance that he is a CF carrier. Despite a 4% chance that Geoff is a carrier, there is a low chance that Anne is, and therefore the chance that their children will have CF is low. Do you think that there is a low, moderate, or high chance that either Geoff or Anne are carriers of a CF mutation? How did you assess this chance?

Anne and Geoff Northern European, Russian Northern European 56 yo yo yo yo high BP (early 40s) diabetes blood clot- leg (54 yo) (mid 40’s) Cystic Fibrosis 34 yo yo yo yo yo yo irritable bowel migraines mitral valve syn.(31 yo) (late teens) prolapse (mid 20’s) 7 yo yo yo yo yo yo born at 37 wks Let’s suppose that Anne reports her ancestry as Northern European. In addition, she reports that her sister’s 4-year-old son has CF. CF carrier screening should indeed be recommended in this situation. We assume that Anne’s sister is a CF mutation carrier based on what we know about autosomal recessive inheritance. Anne’s sister would have inherited the altered CF gene from either of her parents, and as a result, Anne had a 50% chance to have inherited the mutation as well. Anne’s family history of CF increases her chance of being a carrier from the population chance of 4% to 50%. Although Northern European ancestry alone is an indication to recommend CF carrier screening, Anne’s family history is stronger evidence to recommend it. Based on Anne’s result, carrier testing may be indicated in Geoff. Although a diagnosis of CF in one of their children may not change their pregnancy decisions, it would be beneficial for Anne and Geoff to know the diagnosis as close to the birth of their children as possible as the prognosis and management of CF is improved if interventions can be implemented early on. Do you think that there is a low, moderate, or high chance that either Geoff or Anne are carriers of a CF mutation? How did you assess this chance?

Anne and Geoff Factors decreasing risk of being a CF carrier in first scenario Anne’s ancestry has a lower carrier frequency No family history Factors increasing risk of being a CF carrier in second scenario Both Anne and Geoff are of Northern European ancestry Positive family history: Anne’s nephew (second-degree relative) has CF Based on this family history, it seems that Anne is at a low risk to be a CF carrier because of her ancestry. Because Geoff is mostly Northern European, there is a 1 in 25 chance that he is a CF carrier. Despite a 4% chance that Geoff is a carrier, there is a low chance that Anne is, and therefore the chance that their children will have CF is low. CF carrier screening should indeed be recommended in this situation. We assume that Anne’s sister is a CF mutation carrier based on what we know about autosomal recessive inheritance. Anne’s sister would have inherited the altered CF gene from either of her parents, and as a result, Anne had a 50% chance to have inherited the mutation as well. Anne’s family history of CF increases her chance of being a carrier from the population chance of 4% to 50%. Although Northern European ancestry alone is an indication to recommend CF carrier screening, Anne’s family history is stronger evidence to recommend it. Based on Anne’s result, carrier testing may be indicated in Geoff. Although a diagnosis of CF in one of their children may not change their pregnancy decisions, it would be beneficial for Anne and Geoff to know the diagnosis as close to the birth of their children as possible as the prognosis and management of CF is improved if interventions can be implemented early on.

Anne and Geoff Utility of family history tools: Collection
Elicit ancestry of biological grandparents, relevant health information Interpretation Consider red flags: known family history, ethnic predisposition; autosomal recessive inheritance Implementation Assessment of risk determines whether carrier testing is offered; may also consider prenatal testing, pregnancy surveillance, or preparation for CF management

Medical Family History: Tools For Your Practice

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Medical Family History: Tools For Your Practice

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Presentation on theme: "Medical Family History: Tools For Your Practice"— Presentation transcript:

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