Genetic Disorders and the Fetus. Группа авторов

Genetic counseling as a prelude to prenatal diagnosis

      The assumption that noninvasive prenatal testing for common chromosomal abnormalities (see Chapter 7) is a screening and not a diagnostic test, is unfortunately common. Many women receiving a normal report opt to avoid an amniocentesis. The vast majority will be vindicated, but some will complete pregnancy with a child having a disorder that could have been diagnosed in early gestation. Physicians and counselors are advised to remind women of this limitation, given that about half of all chromosomal abnormalities will be missed by the noninvasive screen.⁷⁰³

      Prospective parents should understand their specific indication for prenatal tests and the limitations of such studies. Frequently, one or both members of a couple fail to appreciate how focused the prenatal diagnostic study will be. Either or both may have the idea that all causes of intellectual disability or congenital defects will be detected or excluded. It is judicious for the physician to urge that both members of a couple come for the consultation before CVS or amniocentesis. Major advantages that flow from this arrangement include a clearer perception by the partner regarding risks and limitations, a more accurate insight into his family history, and an opportunity to detect an obvious (although unreported or undiagnosed) genetic disorder of importance (e.g. Treacher–Collins syndrome, facioscapulohumeral dystrophy or one of the orofacial–digital syndromes). Women making an appointment for genetic counseling should be informed about the importance of having their partner with them for the consultation, avoiding subsequent misunderstanding about risks, options, and limitations.

Before prenatal genetic studies are performed, a couple should understand the inherent limitations both of the laboratory studies and, when relevant, of ultrasound. For detection of chromosomal disorders, they should be aware of potential maternal cell admixture and mosaicism (see Chapter 11). When faced with potential X‐linked hydrocephalus, microcephaly, or other serious X‐linked disorders, and the realization of less than 100 percent certainty of diagnosis, couples may elect fetal sex determination as the basis for their decision to keep or terminate a pregnancy at risk. For some, neither chromosomal microarrays, biochemical assays, nor DNA analyses will provide results with 100 percent certainty.

      The time taken to determine the fetal karyotype or other biochemical parameters should be understood before amniocentesis. The known anxiety of this period can be appreciably aggravated by a long, unexpected wait for a result. The need for a second amniocentesis is rarer nowadays but, in some circumstances, fetal blood sampling remains an additional option that may need discussion. Despite the very unlikely eventuality that no result may be obtained because of failed cell culture or contamination, this issue should be mentioned.

      The potential possibility for false‐positive or false‐negative results should be carefully discussed when applicable. Any quandary stemming from the results of prenatal studies is best shared immediately with the couple. The role of the physician in these situations is not to cushion unexpected blows or to protect couples from information that may be difficult to interpret. All information available should be communicated, including the inability to accurately interpret the observations made. This is especially so with the use of the chromosomal microarray (see Chapter 13) and whole‐exome sequencing (see Chapter 14). Cautions are appropriate with special reference to VOUS (see Chapter 14), that require in addition, parental samples to determine inherited or de novo changes.

      Other key issues to be considered by the genetic counselor and discussed when appropriate with the consultand follow.

      Informed consent

      Consent for minor procedures including amniocentesis and CVS has been a requirement for decades and needs no repetition. However, the advent of chromosomal microarrays (see Chapter 13) and whole‐exome sequencing for prenatal diagnosis (see Chapter 14) requires additional explanations and caveats. Informed consent for these two technologies is focused on the potential results, not sampling risks and procedures. The specific issues primarily involve the interpretation of results, their significance, the small possibility of uncertain findings, test limitations, and incidental results.

      Chromosomal microarray testing adds up to 6–10 percent to 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