Genetic Disorders and the Fetus. Группа авторов

when it is found that they are affected,^{225–230, 230, 720} and, at least after a 1‐year follow‐up, potential benefit has been shown even in those found to be at increased risk.⁷²² A European collaborative study evaluated 180 known carriers of the Huntington disease gene mutation and 271 noncarriers, all of whom received a predictive test result. Although the follow‐up was only 3 years for about half the group, pregnancies followed in 28 percent of noncarriers and only 14 percent of carriers.⁷²³ Prenatal diagnosis was elected by about two‐thirds of those who were carriers.

      Genetic counseling for Huntington disease when intermediate alleles with 27–35 CAG repeats are determined, pose significant challenges.⁷²⁴ Intermediate CAG repeats have been associated with behavioral, movement, and cognitive problems.^725–727 The concern is the unpredictable likelihood of expansion which might account for 7 percent of new mutations.⁷²⁴ Providing counseling for those with low penetrance alleles (36–39 CAG repeats) is no less challenging. Repeats in this range are estimated to occur randomly in the general population with a frequency of about 1 in 400.⁷²⁸ For patients with 36–39 repeats considering prenatal diagnosis, many factors will need to be addressed. These include all options discussed earlier and uncertainty, penetrance, anticipation, age of onset, and life expectancy. Experienced geneticists with an established program that includes predictive/presymptomatic testing for Huntington disease should preferably be consulted.

      As others earlier,⁷²⁹ we remain very concerned about the use of a test that can generate a “no hope” result. Even in sophisticated programs offering Huntington disease tests, fewer than expected at‐risk individuals requested testing.⁷³⁰ A multicenter Canadian collaborative study evaluated the uptake, utilization, and outcome of 1,061 predictive tests, 15 prenatal tests, and 626 diagnostic tests from 1987 to 2000. The uptake for predictive testing was about 18 percent (range 12.5–20.7 percent).⁷³¹ Of the 15 who had prenatal tests, 12 had an increased risk, which led to pregnancy termination in all but one.⁷³¹

The motivations leading to the very difficult decision to have or not to have a predictive test are being recognized as extremely complex.⁷³² In a Danish study before DNA tests were available, one in 20 individuals at risk for Huntington disease committed suicide, more than double the population rate,⁷³³ highlighting earlier reports of high suicide rates⁷³⁴ and emphasizing the erosive effects of uncertainty. However, a worldwide assessment of suicide rates, suicide attempts, or psychiatric hospitalizations after predictive testing did not confirm a high rate of suicide.⁷³⁵ In their worldwide questionnaire study sent to predictive testing centers, the authors noted that 44 individuals (0.97 percent) among 4,527 tested had five suicides, 21 suicide attempts, and 18 hospitalizations for psychiatric reasons. All those who committed suicide had signs of Huntington disease, while 11 (52.4 percent) of the 21 individuals who attempted suicide were symptomatic. Suicidal ideation or attempts remain a devastating reality for Huntington disease, especially given the psychopathology in those affected.^{736, 737} Depression, anxiety, and bipolar disorder are not infrequent. Suicidal behavior may be about 12 times that in the population at large, reaching an estimated 20 percent.^{738, 739} Others have written about the psychologic burden created by knowledge of a disabling fatal disease decades before its onset.^740–742

      Hayden⁷⁴³ warned that it is inappropriate to introduce a predictive test that “has the potential for catastrophic reactions” without a support program, including pretest and post‐test counseling and specified standards for laboratory analyses. In one study, 40 percent of individuals tested for Huntington disease and who received DNA results required psychotherapy.⁷⁴⁴ A 5‐year longitudinal study of psychologic distress after predictive testing for Huntington disease focused on 24 carriers and 33 tested noncarriers. Mean distress scores for both carriers and noncarriers were not significantly different but carriers had less positive feelings.⁷⁴⁵ A subgroup of tested persons were found to have long‐lasting psychologic distress. An interview study of 20 who tested negative for Huntington disease revealed reactions that included obvious relief and gratitude, wishes to have (more) children, and life changes that included pursuit of a career and ending an unhappy relationship.⁷⁴⁶ Negative reactions included survivor guilt with sadness and depression or a feeling of pressure to do something extraordinary with their lives.

      Homozygotes for Huntington disease are rare^{747, 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 ADPKD^{751, 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