a prenatal diagnosis result (see Chapter 13) beyond the 8–10 percent for routine karyotyping, and whole‐exome sequencing when done after the ultrasound discovery of fetal structural abnormality adds an additional 6.2–80 percent.691, 704–708 This absurd range reflects very small case series, varying indications, and the presence of single or multiple fetal abnormalities. A more likely detection range would be between 8.5 and 32 percent.707, 708
Prenatal diagnosis using whole‐exome sequencing (see Chapter 14) is primarily focused on pregnancies in which fetal structural abnormality has been observed. A much less frequent indication would be a recent or late diagnosis of a parent with a likely monogenic disorder characterized by genetic heterogeneity. No matter the indication, the informed consent obtained incorporates and extends current practice for chromosomal microarray tests. The decision to offer whole‐exome sequencing will almost inevitably come on the heels of the detection of fetal abnormality and in an atmosphere of tension and anxiety. Any center offering whole‐exome sequencing will have, of necessity, established their informed consent procedure. The following list of pointers are likely to find common ground:
1 Pre‐ and postgenetic counseling by a geneticist or genetic counselor is a prerequisite, with strict adherence to ethical standards.709, 710
2 Both parents should be in attendance.
3 Explanations should use simple language, no jargon, and be in the language of the parents (with an interpreter, if needed).
4 The details of the fetal abnormality, effect on a child (pain; disability), a progressive disorder or not, and life expectancy.
5 The use of targeted sequencing, trios, and gene panels will need explanations, including the reason and need for prior or simultaneous chromosomal microarrays.
6 The time needed to obtain a result.
7 The likely detection rate and the limitations of whole‐exome sequencing (e.g. repeat expansion disorder; mosaicism).
8 The occurrence of false positives, false negatives, or error.
9 The unexpected discovery of nonpaternity or consanguinity.
10 The detection of a variant of unknown significance.709
11 A “secondary finding”711–714 unrelated to the original purpose of the analysis.
12 The opportunity for the parents to opt out of receiving “secondary findings”715 which they should understand may have personal important health implications.
13 The choice to refuse testing.
Presymptomatic or predictive testing
Presymptomatic or predictive testing is available for a rapidly increasing number of disorders, especially neuromuscular and neurodegenerative (see Chapter 14). Huntington disease is the prototype, and predictive testing using guidelines promulgated by the World Federation of Neurology,716–719 the International Huntington Association, and the European Huntington Disease Network719 are well established. Various programs report that a majority of patients are able to cope 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
