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Invited Editorial

Invited Editorial:
Reflections on Phenotype, Syndrome Delineation, and Six Decades of Medical Genetics

John C Carey, MD, MPH, FAAP, FACMG
Division of Medical Genetics, Department of Pediatrics, University of Utah Health, Salt Lake City, UT, USA
Correspondence to: Dr John C Carey      Email: john.carey@hsc.utah.edu

PIC

Dr John C Carey, Professor and formerly Vice Chair of Academic Affairs, Department of Pediatrics at the University of Utah, USA, is one of the most eminent medical genetics experts in the world. Throughout his brilliant career, spanning over 4 decades, he has made many significant clinical and academic contributions to the field of medical genetics particularly in the areas of syndrome delineation and congenital malformations. He was Editor-in-Chief of the American Journal of Medical Genetics from 2001 to 2016. We sincerely thank Dr Carey for accepting our request to write this invited editorial for Genetic Clinics.

Dedication: I dedicate this Commentary to Dr Shubha Phadke, endearingly called “Madam” by her many devoted mentees, who first introduced me to the cultures and richness of India and welcomed me to the community of medical genetics in her beloved nation.

*The key terms in the essay are placed in italics.

One of the many benefits of getting older and remaining in a field is that you advance to an age where your colleagues allow you to compose a paper that is entitled “Reflections on.” Another advantage is that you have the opportunity to have encountered and learned from the pioneers in the discipline. I have had that honor: I entered the field with a deep clinical focus in 1975 at a time before medical genetics was recognized as a specialty of US mainstream medicine. I worked with David W Smith, the perceived patriarch of dysmorphology; John Opitz, the founder of the American Journal of Medical Genetics and a champion in syndrome delineation as well as phenotype analysis; and Victor McKusick, the recognized founder of Medical Genetics. And along this journey I have had the privilege to observe the landmark events in real time. These years of observation and participation ideally position me to “reflect on” where we have been and where we are going in the analysis of phenotype.

In this Commentary, I would like to present one person’s view of the field of Medical Genetics, its rich history, and what I perceive to be the future directions in regards specifically to our study of phenotype and syndrome delineation. I will highlight the key landmarks in Human and Medical Genetics and will propose that since 1960 we have witnessed four Eras (see Table 1). My aim in this discourse is to help us ponder the future challenges in the analysis of phenotype within the context of the remarkable advances that have led to what we now call genomics and its clinical outcome, genomic medicine.


Table 1: The Four Eras of Medical Genetics and Genomics.

Era I: The Golden Era of Phenotype and Syndrome Delineation 1960-2010
Era II: Cloning Disease Genes by the Mapping Approach 1980-2010
Era III: Emergence of Genomic Medicine 2005-present
Era IV: The Modern Era of Phenotype Analysis 2015-present

Any student of Human Genetics is immediately familiar with the historic landmarks that united human genetics and medicine: Mendel’s seminal work of 1865 rediscovered in the early 20th century; Watson and Crick’s recognition of the structure of DNA in 1953; the characterization of the correct number of human chromosomes as 46 in 1956; the recognition that Down syndrome is due to an extra #21 chromosome (1959), and the subsequent rapid emergence of clinical cytogenetics during the 1960s (the key references to these landmarks and those below can be found in Jorde et al., 2019). The observation and description of Edwards syndrome/trisomy 18, Patau syndrome /trisomy 13, and the classical monosomy syndromes (4p-, 5p-, 18p-, and 18q-) paralleled the recognition of now well-established multiple congenital anomaly syndromes during the 1960s (e.g., Smith-Lemli-Opitz syndrome, rediscovery of the de Lange syndrome). Over the ensuing 5 decades cytogenetics technology would advance from various banding types to high resolution banding to the application of florescent DNA probes for specific conditions (e.g., Prader-Willi syndrome) and subtelomeric regions to the current platforms of cytogenomic microarray. I would consider Medical Genetics to have emerged as a medical discipline during that period of the 1960s and 1970s and set the stage for 4 Eras. The first of those eras is what I entitle the “Golden Era of Phenotype and Syndrome Delineation.” Syndrome recognition and description represents, in my opinion, one of the 2 major cornerstones in those early decades of human genetics as it entered mainstream medicine and expanded to medical (and clinical) genetics. Pioneers such as David Smith, John Opitz, Victor McKusick, Judith Hall, and their trainees recognized distinct entities in their clinic settings, described them, and facilitated the process of syndrome delineation. This truly was a time of novel disease discovery; it occurred often within the context of Pediatrics, and would later be referred to as the phenotype-first model. During these years Dr. Smith introduced the term “dysmorphology” (Smith, 1966) hoping that it would replace the potentially pejorative term, teratology, as the study of abnormal structure or altered morphogenesis.

This “Golden Era” proceeded-in my view- from the 1960s until about 2010 when whole exome sequencing introduced the “gene-first” model and significantly changed genetics testing and the methodology of syndrome delineation. I also suggest that the application of exome sequencing (ES) to research, gene discovery, and the clinical setting was not truly a paradigm shift or scientific revolution (Kuhn,1974) because it was the logical extension of the central tenet of biology, i.e., DNARNAprotein. In the late 1970s clinical genetics (while still loosely connected to its parent discipline of pediatrics) and biochemical genetics merged together in the USA under the aegis of Medical Genetics and together with laboratory geneticists (cytogenetics and biochemical) initiated the process of certification of professionals and accreditation of training programs (i.e., the American Board of Medical Genetics). Canada and some countries in Europe established a similar approach.

The 1970s witnessed the rise of prenatal diagnosis by amniocentesis and fetal chromosome analysis as a routine component of obstetric medical care in pregnancy. This continued through the 1970s and into the 1980s until chorionic villus sampling and other prenatal screening modalities, i.e., the triple screen and quadruple screen, emerged and expanded prenatal genetic screening in standard prenatal practice.

Paralleling these advances in syndrome delineation (and prenatal diagnosis) was the emergence of genetic counseling as the other cornerstone of Medical Genetics. While the term had been used long before the 1970s (actually in the 1940s), it was at that time that the development of Master’s level training programs blossomed in the US. A consensus ASHG definition of genetic counseling was proposed in 1975, and soon after, the National Society of Genetic Counselors gained prominence in the field; genetic counseling as a discipline and profession was cemented. By the early 1990s the American Board of Genetic Counseling was established to certify practitioners and accredit training programs.

The second Era began in 1978 with the Alta Conference in Utah led by Drs Botstein, White and Skolnick, who predicted that libraries of DNA polymorphisms could map genes to their chromosome (published in 1980) culminating in 1983 with the mapping of the gene for Huntington chorea to chromosome 4. At first the term “reverse genetics” was used since the approach was the “reverse” of what had existed before, i.e., recognition of genes through their biochemical structure. But in fact, this approach was really forward genetics: the collection of families, the application of technologies to map a gene, and the (then) time-consuming process of gene identification through the convergence of various approaches (animal models, chromosome rearrangements in patients, and gene linkage). Early on, the benefits of gene identification were recognized as clarification of recurrence risks in pregnancies, the application to the genetic counseling process, and the understanding of pathogenesis (hopefully) leading to treatment. This cloning “by the mapping approach” led during the 1980s to the mapping and then recognition of genes for important and classical genetic disorders, i.e., Duchenne muscular dystrophy, cystic fibrosis, neurofibromatosis type 1 (NF1), and Marfan syndrome. By the 1990s, genes for over 2000 diseases had been mapped or cloned, and the explosion in recognition of cancer genes (e.g. BRCA1 and 2) occurred that propelled the rise of cancer genetics as a bone fide area of the field. These advances often occurred in the context of the Human Genome Project, which was initiated in 1990, and by 2001 a 90% draft of the human genome had been completed. Soon, it was common for review articles to display a map where one could see the location and gene identification of genes for various syndrome types, e.g., malformation syndromes, skeletal dysplasias, and more. Certainly, the stories of the mapping and then identification of a gene are rich narratives, each having their own lessons, and all worth retelling. Each story contains its own bends and turns often involving rich collaborations and at other times secrecy and press releases. NF1 is a particularly interesting example (Carey, 2017): using the approach that was widely available in mid 1980s, the gene for NF1 was mapped by 2 different sets of collaborators in 1986. At the time that the mapping located the causative gene to the pericentric region of 17q11, two patients with NF1, who had balanced translocations involving 17q11 were identified and helped lead to the sequencing of the full-length cDNA that was labeled NF1 with its encoded protein, the NF1 peptide. At that point in history, the excitement surrounding finding the patients with these translocations cannot be underemphasized. Similar stories where translocations in patients seen in clinic settings (e.g., Waardenburg, van der Woude, Sotos) helped identify other disease genes are commonly known in the field. The promise, of course, in recognizing NF1 and its peptide would be treatment. But it took another 15 years for clinical trials surrounding the treatment of malignant peripheral nerve sheath tumors and cognitive disabilities to come forward. This is not the correct forum to review all that has come about in regards to treatment of genetic disease because my focus here is primarily on phenotype and syndrome delineation, but clearly the importance of treatment and gene therapies (and now with gene editing) cannot be overstated.

By the late 1990s, mainstream medicine in the US witnessed the creation of the American Board of Medical Genetics (eventually American Board of Medical Genetics and Genomics) the American College of Medical Genetics (1991), the American Board of Genetic Counseling (1993), and Medical Genetics Residencies by the early 2000s. Similar austere organizations emerged as well in Canada and Europe.

The third Era is one that I label Genomic Medicine. In this light I cite the famous Chinese proverb “May you live in interesting times.” The emergence of genomic medicine in the last decade or so certainly would qualify us as living in “interesting times.” Genomic medicine overlaps what others later refer to as personalized healthcare or individualized healthcare. Genomic medicine is defined by the NIH in the US as an emerging “discipline that involves genomic information about the individual as part of clinical care”. Various components would include the systematic implementation of studying Mendelian disease, pharmacogenomics, and the application of clinical ES and whole genome sequencing to clinical care. Certainly, ES and genome sequencing (Next generation sequencing, NGS) are unparalleled in this observer’s mind to any approach or technique that had entered the field since cytogenetics. In the early part of the 2010 decade, the ability to identify the gene for a condition using ES became remarkably rapid and depended on having only a few patients with the condition. This advance led to an explosion in gene discovery in known phenotypes (e.g., Miller acrofacial dysostosis, Kabuki syndrome). It was followed closely by the identification of novel syndromes by applying the approach to various clinical presentations (e.g., intellectual disability, multiple congenital anomalies); the “gene first” model had emerged. What occurred then was unprecedented: a condition was identified first through its etiology and the characterization of its full phenotypic spectrum and its clinical variability would follow with additional reports. The concern at the time by traditional clinical geneticists (including myself) was that trainees and junior practitioners would rely solely on the molecular testing and lose the clinical skills needed to characterize phenotypic signs, generate a relevant differential diagnosis, establish a clinical diagnosis, and interpret the variants. As wisely foreseen by Hennekam and Biesecker (2012), that scenario has not turned out to be the case. I would concur: delineation of the phenotype now depends on modern phenotypic analysis. It is my contention that we then entered Era IV, the Modern Era of Phenotype Analysis.

The current Era is indeed exciting and interesting. I recently suggest in the review article on phenotype that, “… there has likely never been a more exciting time in the history of medicine” as phenotype analysis in all medical specialties has become paramount. In the review (Carey, 2017) I highlight the principles, history, definition, and current strategies to define phenotype and point to the advent of a “Human Phenome Project”. Approaches (such as Phenotips in the clinical setting and electronic medical record), facial recognition technologies (such as Face2Gene), and online resources that link clinicians, families, and researchers (such as MyGene2) have changed the landscape in which clinical geneticists practice medical genetics and characterize syndrome delineation. These approaches have heralded a modern era in phenotype analysis. Comprehensive characterization of phenotype, in my view, is increasingly becoming valued by research scientists, laboratory geneticists, and clinicians of all specialties. In the interpretation of NGS, the importance of curating both the phenotypic findings and the DNA variants in making sense of the results and inferring causation is widely recognized (Friedman et al., 2020).

To conclude, these milestones make this observer optimistic about the future directions of phenotype analysis and syndrome delineation. The continuation, however, of this current trajectory will depend on the wholehearted acceptance of medical genetics as a vital component of mainstream medicine.

References

1.    Carey JC. Phenotype analysis of congenital and neurodevelopmental disorders in the next generation sequencing era. Am J Med Genet Part C Semin Med Genet 2017;175C:320–328.

2.    Friedman JM, et al. Exome sequencing and Clinical Diagnosis. JAMA 2020; 324:627–628.

3.    Hennekam RC, Biesecker LB. Next-generation sequencing demands next-generation phenotyping. Hum Mutat 2012; 33: 884–886.

4.    Jorde LB, et al. Medical Genetics 6th edition. Elsevier (Mosby) 2019.

5.    Kuhn TS. The Structure of Scientific Revolutions, 2nd edition. University of Chicago Press, Chicago, IL 1974.

6.    Smith DW. Dysmorphology (teratology). J Pediatr 1966; 69:150–169.