Genetic Disorders and the Fetus. Группа авторов

to have noninvasive prenatal testing, often blissfully unaware that about half of all chromosomal abnormalities detectable through amniocentesis or CVS and authoritatively discussed, would be missed. There is room for concern given the current consensus that all women should be offered either of these two procedures.

      Similarly, all women with risks of having offspring with a monogenic disorder and a known pathogenic variant should be informed about and offered the option of preimplantation genetic testing (PGT). The extensive and long‐established experience of the authors with PGT enshrine this recommendation. Expanded carrier screening should make this a more frequently addressed option. Couples should, however, be carefully counseled about the limitations of such screening. All the facts, figures, guidelines, and recommendations have been updated in this edition, and will assist the expanded healthcare team in providing optimal care to all patients.

      Coupled with remarkable advances in technology, prenatal diagnosis has undergone a revolution. Thus far, and continually increasing, more than 4,331 culprit genes and 6,739 associated phenotypes for an extensive array of genetic disorders have been identified. Consequently, since physicians in all medical specialties encounter genetic disorders for which a molecular diagnosis is available, awareness of the options for prenatal diagnosis or PGT has become especially important.

      Pari passu with these technical advances has come the opportunity to avoid and prevent the occurrence of many lethal and seriously disabling genetic diseases. This progress means that physicians in all specialties incur responsibility (and inevitable liability) to acquire new knowledge of genetic disorders and offer appropriate tests or refer patients for evaluation and genetic counseling.

      More than 60 million people worldwide are estimated to have DNA studies in the next 5 years. Expanded carrier testing, maternal cell‐free plasma DNA testing, whole‐exome sequencing, next‐generation sequencing, single‐cell molecular diagnosis, and advanced fetal imaging, all fully presented in this volume, now complement the well‐established procedure for prenatal diagnosis and PGT. Whole‐genome analysis for prenatal diagnosis (even if advisable) simply awaits further technical advances.

      Chromosomal microarrays and whole‐exome sequencing have propelled an even greater prenatal diagnostic reach, especially in the face of fetal structural, including skeletal, abnormalities, given the advances in ultrasound and magnetic resonance imaging, so expertly covered in this volume by authors from three European countries.

The fetal anomaly scan has to an important extent superseded amniotic fluid α‐fetoprotein for the diagnosis of neural tube defects. Nevertheless, the significant worldwide prevalence of neural tube defects makes maternal serum α‐fetoprotein screening a continuing vital test, critically evaluated here by a pioneer. The diagnosis of neural tube defects and their consequences, as well as the frequently failed efforts at prevention, are thoroughly detailed.

      Knowledge of the common sex chromosome aneuploidies and some of the rarer variants continues to expand. Up‐to‐date summaries of all these disorders are presented with specific recommendations for genetic counseling. Molecular prenatal diagnosis has now become routine and the multiple technologies utilized, with their benefits and limitations along with clinically based caveats and considerations, are presented in a significantly updated chapter.

      The advent of next‐generation sequencing has, by targeting panels or whole‐exome approaches, resulted in more opportunities for avoidance and prevention through prenatal diagnosis. These widely available technologies not only address previously diagnosed childhood‐onset disorders, but also those of adult onset, including cardiomyopathies, malignancies, and neurologic disorders.

      Progress and refinement in the diagnosis and management of a wide range of metabolic disorders are fully and authoritatively updated, and equally complemented by the detailed in‐depth advances in molecular diagnostics that include the hemoglobinopathies, fragile X syndrome, cystic fibrosis, disorders of folate metabolism, and the immunodeficiency diseases.

      Pregnancy termination is a sad but fortunately uncommon consideration following prenatal diagnostic studies. The techniques and complications are fully discussed and complemented by insightful senior experience with the management of grief after pregnancy and perinatal loss. Discussion about the care and management of mothers with genetic disorders that affect fetal health and those who transmit infection to the fetus is sharply focused on diagnosis, prevention, avoidance, and treatment. Fetal health is doubly important given the known fetal origins of adult disease that go far beyond hypertension, obesity, and diabetes, to include the epigenetic phenomena induced by the maternal pregnancy environment. A thorough exposition on the importance of placental development, structure, function, genetics, and pathology on fetal growth and development is expertly presented in this edition. Steadily, but surely, fetal gene therapy via hematopoietic stem cell transplantation is taking root, while a remarkable chapter on fetal surgery by a leader in the field points to new brave surgical remedies.

      While all authors acknowledge continuing progress in molecular genetics, inconclusive results due to variants of uncertain significance are not infrequent. Laboratory conclusions can be further compounded by a host of issues that potentially befuddle interpretation. Commonly encountered issues include delineation of normal variation or polymorphisms, difficulty determining the pathogenicity of variants, depth of sequencing coverage, regions of high GC content, mosaicism, DNA contamination, digenic inheritance, locus heterogeneity, and false‐positive and false‐negative results. The concurrence of an incidental (secondary) finding on fetal DNA analysis will predictably arouse great parental anxiety.

      Current laws and public policy regarding prenatal diagnosis and PGT in 16 countries are examined in detail regarding international differences, with special reference to the guidelines relevant to the emerging technologies. A senior physician‐lawyer, in reviewing the important principles in the torts of wrongful birth and wrongful life, focused on the potential liability of those involved in reproductive medicine. Professional ethics in obstetrics, with emphasis on the ethical principles of beneficence and autonomy and the ethical concept of the fetus as a patient, receive in‐depth discussion by doyens in this field.

      This volume is a major repository of facts about prenatal diagnosis and provides a critical analysis and synthesis of established and new knowledge based on the long experience of the senior contributing authorities in their respective fields. In addition, a broad international perspective is presented with contributions from recognized international experts from nine countries. The guidance provided and the insights and perspectives of these authors make this volume a valuable and indispensable resource for all those whose focus is securing fetal health through prenatal diagnosis or PGT.

This text is very well referenced and replete with evidence‐based guidance and reflective of the lifetime experience and wisdom of distinguished senior authors. This edition encompasses 152 tables, 167 figures, and over 10,000 references. A valuable index will facilitate the reader's search for specific information.

      The major technologic advances in genetics have made the requirement for preconception, prenatal, and perinatal genetic counseling of paramount importance. Even though the underlying principles and prerequisites are well established, the many advances have introduced a panoply of new challenges discussed in detail in a comprehensive, heavily referenced opening chapter. We are in the golden era of human genetics, and through new discoveries and insights have increased opportunities for the diagnosis, prevention, and treatment of many serious and lethal genetic disorders.

      Aubrey Milunsky and Jeff M. Milunsky

      Cambridge

Acknowledgments

      This eighth edition marks the 42nd year of this text and reflects the continuing remarkable advances made in achieving accurate prenatal and preimplantation diagnoses. The first book on this subject (The Prenatal Diagnosis of Hereditary Disease) was published some 48 years ago (by AM). The distillation of accrued biological, technological, ethical, and legal knowledge has graced these pages and enriched the reference value of these editions. The wisdom, insight, perspective, expertise, experience, and knowledge of these senior contributing authors has made these volumes