The presence of certain birth defects (also known as congenital anomalies), mental retardation, and/or other characteristic features can raise the level of suspicion that an individual is affected with a genetic syndrome or chromosome abnormality. When possible, the identification of a cause for the congenital anomalies and/or mental retardation in an individual not only allows for genetic counseling regarding recurrence risk but can also be important, psychologically and practically, for the individual and family. The evaluation of an individual to rule out the presence of a genetic condition often involves the evaluation of that individual by a medical geneticist. Certain biochemical, molecular, cytogenetic, and physiologic tests may also be helpful. The genetic counselor can be an important part of the health-care team that evaluates and cares for the patient. The counselor can aid the geneticist in his or her clinical evaluation of the patient, help to coordinate further testing, and help to keep the patient and/or family apprised of the need for such testing. The counselor can also help to keep the family informed of the possible conditions in the differential diagnosis, assist in discussing test results, and support the individual and/or family emotionally.

Although beyond the scope of this book, it is important to recognize that genetic counselors routinely interact with individuals who have a personal or family history of a genetic syndrome. It is, therefore, also important to be acquainted with the more common patterns of inheritance:

In genetic syndromes that follow an autosomal recessive pattern of inheritance, a carrier has one copy of a genetic alteration, or mutation, and, as a general rule, does not exhibit symptoms of that syndrome. If both members of a couple are carriers of an autosomal recessive disorder, there is a 25% chance for them to have an affected child in each pregnancy. Examples of autosomal recessive conditions include cystic fibrosis, which results in thickened mucus primarily affecting the lungs, digestive tract, and male reproductive tract; and Tay-Sachs disease, a fatal neurodegenerative disorder that is more common in the Ashkenazi Jewish, Cajun, and French-Canadian populations.

In autosomal dominant inheritance, there is a 50% chance for an affected individual to transmit the disease-causing mutation to each of his or her offspring. Depending upon the particular condition, inheriting the mutation might or might not mean that an individual will show features of that condition, a phenomenon known as incomplete or reduced penetrance. Additionally, there can be a wide range of clinical severity, even within a family; this is known as variable expressivity. Examples of autosomal dominant conditions include Huntington’s disease, an adult-onset neurodegenerative condition, and Marfan syndrome, a condition that affects connective tissue.

In X-linked recessive inheritance, there is a 50% chance for each son of a female carrier to be affected and a 50% chance for each daughter of a female carrier to be a carrier herself. Under certain uncommon circumstances, females can be affected with X-linked recessive conditions. As in autosomal recessive inheritance, carriers have one mutation, except in this case on one X chromosome instead of on an autosome, and generally do not exhibit features of the condition. Examples of conditions that follow an X-linked recessive pattern of inheritance include fragile X syndrome, which is the most common inherited form of mental retardation (see Chap. 19), and hemophilia, a bleeding disorder.

In X-linked dominant inheritance, there is a 50% chance for each child of an affected woman to inherit the disease-causing mutation. Affected females tend to be more common and are often less severely affected than are affected males; X-linked dominant conditions, particularly those that are rare, can be prenatally lethal in affected males. Incontinentia pigmenti type 2, which affects the skin, skin derivatives, and central nervous system, is an X-linked dominant condition that is frequently lethal in affected males [8].

In multifactorial inheritance, a genetic predisposition increases the chance that an individual will develop a particular condition. Certain environmental factors, such as diet and exercise, also have a role in determining if the individual will be affected. Examples of multifactorial conditions are diabetes, heart disease, and neural tube defects. Generally speaking, the more distant the degree of relationship between the individual in question and the affected relative, the lower the recurrence risk, until such risk approximates that of the general population.

In the majority of cases, cancer is sporadic in an individual. However, in some families, a genetic predisposition to cancer significantly increases the chance to develop the condition. Hallmarks of hereditary cancer families include relatively early-onset cancer as compared to the general population, bilateral or multiorgan cancer, multiple affected family members (usually following an autosomal dominant pattern of inheritance), and unusual cancer or the presence of certain characteristic clinical features. When an individual is referred for cancer genetic counseling, the genetic counselor educates the counselee about the genetics of cancer predisposition. Based on personal and family history information, the counselor also provides a risk assessment for cancer or for a hereditary cancer predisposition. The risks, benefits, and limitations of appropriate, available molecular testing options and research opportunities are discussed, as are the potential results and their possible psychosocial and practical implications. Options for cancer risk reduction, such as prophylactic surgery, chemoprevention, and cancer screening, are also likely to be reviewed.

As discussed in Chap. 15, certain translocations are characteristic of certain cancers. For example, the (9;22) translocation, which results in the “Philadelphia chromosome” and the fusion of two genes, BCR and ABL1, is associated with chronic myelogenous leukemia (CML). Similarly, Burkitt lymphoma is associated with an (8;14) translocation. The identification of cytogenetic abnormalities in a cancer patient can have important diagnostic and prognostic implications and can also play a role in designing a treatment strategy [8, 9]. Occasionally, when chromosome analysis is performed for the indication of a hematological abnormality, a chromosome abnormality that may be constitutional is identified. In such a situation, this should be verified, and, if true, the patient should be counseled about the finding and the associated implications, not only for him- or herself, but for other family members as well [9].

When both members of a couple share at least one common ancestor, they may be referred to a genetic counselor to discuss the possibility for an increased risk of birth defects and/or genetic conditions in their offspring. Using information about the degree of relationship between the members of the couple, their ethnicities, and family history, the counselor discusses the potential for increased risk, if any, and offers any appropriate options for carrier and/or prenatal testing [10]. Although in some cultures consanguinity is accepted and even common, in other cultures, it carries a social stigma. Not only might a consanguineous couple be dealing with an increased risk of abnormalities in their offspring, but they might also be facing criticism from their family and society. In these situations, the genetic counselor can provide emotional support and referral to an appropriate support organization.

The chance of having a pregnancy or child affected with a chromosome abnormality increases with advancing maternal age (Table 21.1) [11, 12, 14]. While previous standard of care required that prenatal diagnosis (see Chap. 12) via chorionic villus sampling (CVS) or amniocentesis be offered to all pregnant women who will be 35 or older at their estimated date of delivery (EDD), it is now recommended that such diagnostic testing be offered to all women, regardless of age [14–16].

Advanced paternal age, frequently defined as 40 or older at the time of conception, is an acceptable, although infrequent, reason for a referral to a genetic counselor. Studies have shown an increased risk for genetic defects associated with advanced paternal age. These genetic defects include sporadic, dominant single gene mutations, most commonly Pfeiffer syndrome, Crouzon syndrome, Apert syndrome, achondroplasia, thanatophoric dysplasia, and MEN2A and MEN2B. The risk for a sporadic, autosomal dominant genetic syndrome in the offspring of men over the age of 40 is presently felt to be less than 0.3–0.5%. Studies also indicate that advanced paternal age may be associated with an increased risk of complex conditions, including some birth defects, schizophrenia, autism spectrum disorders, and some cancers. There does not, however, appear to be an increased risk of chromosome abnormalities associated with advanced paternal age with the possible exception of trisomy 21 and Klinefelter syndrome. Most of the paternal age-related birth defects cannot be reliably detected by prenatal diagnosis [17].

Screening can be used, along with maternal age, to estimate the possibility that a fetus is affected with Down syndrome or trisomy 18. Such aneuploidy screening can be performed through the utilization of ultrasound, maternal serum, or, frequently, a combination of the two.

The term “teratogen” applies to any medication, chemical, or environmental agent that has the potential to cause adverse effects, such as birth defects, on a developing fetus. When the mother or father of a current or future pregnancy has been exposed to an agent that could have a detrimental effect on that pregnancy, a referral to a genetic counselor is appropriate. Of note, certain maternal conditions, such as phenylketonuria (PKU), which is an inherited metabolic disorder, diabetes, and seizure disorders increase the risk for birth defects in a pregnancy. The counselor will consult current resources and discuss with the exposed individual or couple the potential adverse effects associated with the exposure in question. Any available options for minimizing these potential adverse effects or for identifying them prenatally are also discussed.

Certain chromosome abnormalities and genetic conditions result in varying degrees of infertility (see Chap. 11). Therefore, when an individual or couple experiences infertility, it is appropriate to rule out the possible genetic and cyto-genetic causes. If such a cause is identified, a genetic counselor can be important in educating the individual about the condition. The genetic counselor can also assist the physician in discussing the available options that could allow for reproduction. In addition, if the individual is able to reproduce using his or her own gametes, the possible recurrence risks for future offspring should be addressed.

Miscarriage is more common than many people recognize. In fact, it is estimated that 10–15% of all recognized pregnancies end in miscarriage [18]. There are many possible causes of miscarriage, including a chromosomally abnormal conceptus. Approximately 50% of recognized first trimester miscarriages are chromosomally abnormal [8, 18, 19]. In some individuals, pregnancy loss is recurrent. In addition to having the potential to cause significant psychological distress, recurrent miscarriage warrants a complete evaluation, which could include genetic, cytogenetic, and endocrinology studies, in an attempt to identify the cause. As discussed later, some causes of recurrent miscarriage confer increased reproductive risks for the patient, as well as his or her family members.

As previously mentioned, congenital anomalies, mental retardation, developmental delay, or certain characteristic features are all examples of indications for chromosome analysis. Several chromosome abnormalities are detectable through conventional chromosome analysis, while others, such as microdeletion syndromes, require specialized analysis, such as fluorescence in situ hybridization (FISH) (see Chap. 17) or microarray (see Chap. 18). The following is a brief introduction to several of the more common chromosome abnormalities encountered in genetic counseling. The style of genetic counseling associated with the identification of a chromosome abnormality often varies depending upon the age of the affected individual. Although the clinical information is unlikely to be significantly different, the tone of the discussion often varies depending on whether the diagnosis is made prenatally, when termination of the pregnancy might be an option, or during childhood, adolescence, or adulthood. As previously mentioned, regardless of whether a chromosome abnormality is diagnosed prenatally or postnatally, the genetic counselor often plays a role in educating the patient or family about the clinical features of the condition, recurrence risks, and available supportive treatments. Although the identification of a cause for the phenotypic abnormalities in an individual can be an empowering event for the patient and family, it can also induce significant stress. The genetic counselor, acting as a member of the team caring for the individual, often plays an important role in helping the family to cope with the diagnosis both practically and emotionally.