or a feeling of pressure to do something extraordinary with their lives.
Homozygotes for Huntington disease are rare747, 748 and reported in one out of 1,007 patients (0.1 percent). Counseling a patient homozygous for Huntington disease about the 100 percent probability of transmitting the disorder to each child is equivalent to providing a nonrequested predictive test,749 while failing to inform the patient of the risks would be regarded as the withholding of critical information. Pretest counseling in such cases would take into consideration a family history on both sides and therefore be able to anticipate the rare homozygous eventuality.
On the other hand, an increasing number of examples already exist (see Chapter 14) in which presymptomatic testing is possible and important to either the patient or future offspring or both. Uptake has been high by individuals at risk, especially for various cancer syndromes.750 Use of DNA linkage or mutation analysis for ADPKD751, 752 may lead to the diagnosis of an unsuspected associated intracranial aneurysm in 8 percent of cases (or 16 percent in those with a family history of intracranial aneurysm or subarachnoid hemorrhage753) and preemptive surgery, with avoidance of a life‐threatening sudden cerebral hemorrhage. It is worth noting that a subgroup of families has features similar to Marfan syndrome and that haplo‐insufficiency of the PKD1 gene influences the transforming growth factor‐β (TGFβ) signaling pathway.754 In a study of 141 affected individuals, 11 percent decided against bearing children on the basis of the risk.755 These authors noted that only 4 percent of at‐risk individuals between 18 and 40 years of age would seek elective abortion for an affected fetus. The importance of accurate presymptomatic tests for potential at‐risk kidney donors has been emphasized.756 Organ donation by a sibling of an individual with ADPKD, later found to be affected, has occurred more than once. Since the PKD1 gene abuts the tuberous sclerosis (TSC2) gene, heterozygous deletions may lead to a contiguous gene‐deletion syndrome.757
Individuals at 50 percent risk for familial polyposis coli (with inevitable malignancy for those with this mutated gene) who undergo at least annual colonoscopy could benefit from a massive reduction in risk (from 50 percent to <1 percent) after DNA analysis. Individuals in whom this mutation was found with greater than 99 percent certainty may choose more frequent colonoscopies and eventually elective colonic resections, thereby saving the lives of the vast majority. The need for involvement of clinical geneticists is especially evident in this and other disorders in which complex results may emerge. Giardiello et al.758 showed that physicians misinterpreted molecular test results in almost one‐third of cases.
Families with specific cancer syndromes, such as multiple endocrine neoplasia, Li–Fraumeni syndrome, or von Hippel–Lindau disease, may also benefit by the institution of appropriate surveillance for those shown to be affected by molecular analysis when they are still completely asymptomatic, once again, in all likelihood, saving their lives. In one case, an evaluation using array comparative genomic hybridization to determine the cause of intellectual disability revealed a de novo deletion within 3p25.3 that included the von Hippel–Lindau gene.759 For example, elective thyroidectomy is recommended for multiple endocrine neoplasia type 2B by 5 years of age in a child with this mutation, given the virtual 100 percent penetrance of this gene and the possible early appearance of cancer.760 Predictive testing, even of children at high genetic risk, poses a host of complex issues.761 Where life‐threatening early‐onset genetic disorders are concerned, testing in early childhood still requires the exercise of parental prerogatives. However, failure to test because of parental refusal may invite the reporting of child neglect.762
Identification of specific mutations in the breast/ovarian cancer susceptibility genes (BRCA1 and BRCA2) has led to us providing requested prenatal diagnosis. Mothers with such mutations who have seen their own mothers and sisters die have made the difficult personal decision to terminate pregnancy.763 DudokdeWit et al. laid out a detailed and systematic approach to counseling and testing in these families.764 In their model approach, important themes and messages emerge:
Each person may have a different method of coping with threatening information and treatment options.
Predictive testing should not harm the family unit.
Special care and attention are necessary to obtain informed consent, protect privacy and confidentiality and safeguard “divergent and conflicting intrafamilial and intergenerational interests.”
A French study noted that 87.7 percent of women who were first‐degree relatives of patients with breast cancer were in favor of predictive testing.765 Two specific groups of women are especially involved. The first are those who, at a young age, have already had breast cancer, with or without a family history, and in whom a specific mutation has been identified. Recognizing their high risk for breast and/or ovarian cancer,766, 767 these women have grappled with decisions about elective bilateral mastectomy and oophorectomy and mastectomy of a contralateral breast. Current estimates of penetrance are 36–85 percent lifetime risk for breast cancer and 16–60 percent lifetime risk for ovarian cancer, depending upon the population studied.768
The second group of women are of Ashkenazi Jewish ancestry. These women have about a 2 percent risk of harboring two common mutations in BRCA1 (c.68 69delAG and c.5266dupC) and one in BRCA2 (c.5946delT) that account for the majority of breast cancers in this ethnic group.768, 769 Regardless of a family history of breast or ovarian cancer, the lifetime risk of breast cancer among Jewish female mutation carriers was 82 percent in a study of 1,008 index cases.770 Breast cancer risk by 50 years of age among mutation carriers born before 1940 was 24 percent, but 67 percent for those born after 1940.770 Lifetime ovarian cancer risks were 54 percent for BRCA1 and 23 percent for BRCA2 mutation carriers.770
It can easily be anticipated that, with identification of mutations for more and more serious/fatal monogenic genetic disorders (including cardiovascular, cerebrovascular, neurodegenerative, connective tissue, and renal disorders, among others), prospective parents may well choose prenatal diagnosis in an effort to avoid at least easily determinable serious or fatal genetic disorders. Discovery of the high frequency (28 percent) of a mutation (T to A at APC nucleotide 3920) in the familial adenomatous polyposis coli gene among Ashkenazi Jews with a family history of colorectal cancer771 is also likely to be followed by thoughts of avoidance through prenatal diagnosis. This mutation has been found in 6 percent of Ashkenazi Jews.771 Because of the ability to determine whether a specific cancer will develop in the future, given identification of a particular mutation, much agonizing can be expected for many years. These quandaries will not and cannot be resolved in rushed visits to the physician's office as part of preconception or any other care. Moreover, developing knowledge about genotype–phenotype associations and many other aspects of genetic epidemiology will increasingly require referral to clinical geneticists.
Expansion mutations and anticipation
In 1991 the first reports appeared of dynamic mutations resulting from the unstable expansion of trinucleotide repeats.772 Thus far, at least 40 proven disorders with these unstable repeats have been described (see Chapter 14).773 All disorders described thus far are autosomal dominant or X‐linked, except for Friedreich ataxia and progressive myoclonic epilepsy with myoclonic tremor,774–776 which are autosomal recessive and also unique in having intronic involvement.777 Typically for these disorders (except for Friedreich ataxia), the carrier will have one normal allele and a second expanded allele. The repeat expansion disorders, although diverse, share many basic features. They arise from
