DOI: 10.1590/1413-812320182410.19102019 3607 A r

How diseases became “genetic” A rtTigo icle

Como as doenças se tornaram “genéticas”

Ilana Löwy (https://orcid.org/0000-0001-6963-0578) 1

Abstract This article examines the origins of the Resumo O presente artigo tem o objetivo de exa- term “genetic disease.” In the late 19 and early 20th minar as origens do termo “doença genética. No century, an earlier idea that diseases that occur in final do século XIX e início do XX, a vaga ideia families reflect a vague familiar “predisposition” que a doença manifesta entre familiares refletia was replaced by the view that such diseases have uma “predisposição” familiar, foi substituída pela specific causes, while Mendelian genetics provided visão que essas doenças possuem causas específi- then clues to the patterns of their transmission. cas, enquanto a genética mendeliana forneceu as The genetictisation of inborn pathologies took pistas para os padrões de transmissão da doença. a decisive turn with the redefinition, in 1959, of A genética das patologias congênitas deu uma Down syndrome as a chromosomal anomaly, then guinada decisiva, em 1959, com a redefinição da the development of tests for the diagnosis of other Síndrome de Down como uma anomalia cromos- hereditary pathologies. At that time, geneticists sômica e, depois, com o desenvolvimento de testes distinguished “hereditary” diseases that run in para o diagnóstico de outras patologias hereditá- families, from “genetic” conditions that are the rias. Naquela época, os geneticistas distinguiam result of new mutations during the production of doenças “hereditárias” como aquelas que acome- egg and sperm cells. In the latter case, the inborn tiam os elementos de uma família, de condições impairment is produced by an anomaly in the “genéticas” que são o resultado de novas mutações genetic material of the cell, but is not hereditary, ocorridas durante a produção dos óvulos e esper- because it is not transmitted from one or both pa- matozoides. Neste último caso, a deficiência inata rents. In the late 20th and early 21st century, new é causada por uma anomalia do material genético genomic technologies blurred the distinction be- da célula, porque não é transmitida por qualquer tween hereditary and genetic impairments, exten- um ou ambos os pais. No final do século XX e iní- ded the concept of genetic disease, and modified cio do XXI, as novas tecnologias genômicas obs- the experience of people living with such a disease. cureceram a distinção entre deficiências hereditá- 1 CERMES 3 Paris & visiting professor - Instituto Key words Heredity disease, Genetic disease, ria e a genética, estenderam o conceito da doença de Medicina Social, Down syndrome, Genomic technologies genética e modificaram a experiência das pessoas Universidade Estadual do que vivem com esse tipo de doença. Rio de Janeiro. R. Francisco Xavier 524/bl. D/7º, Palavras-chave Hereditariedade, Genética, Cro- Maracanã. mossomos, Síndrome de Down, NIPT 20550-013 Rio de Janeiro RJ Brasil. [email protected] 3608 Löwy I

Hereditary diseases before genetics quired traits. Another British psychiatrist, Alfred Frank Tredgold (1870-1952) whose Textbook of An interest in traits that children inherit from Mental Deficiency, first published in 1908, then their parents – the father’s hair, the mother’s actualized and reedited until the author’s death, eyes – may be as old as civilizations, but inter- became a key source of knowledge on this ques- est in diseases that run in families is document- tion in the English-speaking world, put the ac- ed from the 17th century on, when physicians cent on the role of “pathological heredity” in pro- started to systematically record families with an ducing “feeble mindness”. Mental impairment, unusual concentration of abnormal traits1,2. The Tredgold believed, is nearly always “hereditary,” search for “morbid heredity” was intensified in a broad term which included advanced parental the 19th century. At that time, this concept in- age, alcoholism, syphilis and tuberculosis. Tred- cluded a multiplicity of causes, such as familial gold included the last two pathologies among traits (“likes begets likes”) intensified by inter- causes of hereditary “feeble mindness”, because, marriage, but also alcoholism, tuberculosis, and he argued, the geneticists’ claim that infectious venereal diseases, especially syphilis. Tubercu- diseases do not affect “germ plasm” is not plausi- losis and syphilis were classified as “hereditary ble. It is difficult to believe that a systemic disease causes” of pathologies because, until mid-20th such as tuberculosis does not degrade the quality century, the term “heredity,” especially in its lay of sperm and egg cells9. At first, Tredgold was a uses, englobed all the elements that could affect moderate eugenist. He did believe that the ma- the “quality of the seed” and fetal development. jority of inborn impairment were inherited, but Maternal conditions that may affect the fetus, also that society cannot do much to prevent them, such as syphilis, tuberculosis or alcoholism could mainly because impaired children are frequently therefore be described as “hereditary”3. born to parents who do not display marked signs In late 19th and early 20th century physicians – of “degeneration”. In the 1930s, perhaps under especially those linked with the rapidly growing the influence of ideas propagated by the German eugenic movement – were concerned by hered- Nazi and their British sympathizers, Tredgold ity of “feeble mindness”, and its potential threat changed his mind, and converted to the idea that to society4-7. The British psychiatrist George the sterilization of selected categories of “degen- Edward Shuttleworth (1842-1928), author of erates «and the prohibition of marriage of people the textbook, Mentally Deficient Children: Their from “tainted” families›› will reduce the burden Treatment and Training, proposed to distinguish of hereditary diseases in society”10. between “acquired mental deficiency,” produced Tredgold views on the effectiveness of eugen- by accidents of childbirth or childhood by events ic interventions such as sterilization to reduce such as trauma, a febrile disease or intoxication, the frequency of “feeble mindness” were strongly and “inborn mental deficiency,” produced before opposed by the British geneticist, Lionel Penrose birth by “formative defects”. Shuttleworth in- (1898-1972). Penrose coordinated in the 1930s a cluded in the latter category conditions such as large study on the possible inheritance of men- microcephalus (too small brain), hydrocephalus tal conditions, the Colchester Survey. In the final (the accumulation of liquid in the skull), “mon- report of this survey Penrose explained that very gol” feeblemindedness, (today, Down syndrome), few mental disorders, were truly “hereditary” that “cretinism” (today, thyroid insufficiency), and is, followed a Mendelian pattern of transmis- anomalies produced by diseases of the pregnant sion11. Among the latter he singled out two dis- woman, such as epilepsy, syphilis and eclampsia eases, Huntington’s chorea and phenylketonuria (seizures during pregnancy). Mental deficien- (PKU), both undoubtedly hereditary – and very cy which stems from “formative defects” (that rare. Penrose was especially interested in PKU, is, impairments acquired before birth) Shuttle- seen by him as an exemplary hereditary patholo- worth pointed out, is frequently associated with gy. PKU is produced by the organism’s decreased visible physical defects such as hare lip, deficient ability of metabolize the amino acid phenylal- ear lobes, missing fingers, unusual shape of face anine. The accumulation of phenyl alanine in or crane anomalies. A trained physician should the blood leads to intellectual impairment, sei- be able to recognize the physical traits of mental zures and behavioral problems. This condition deficiency even in relatively mild cases. Such traits was first described by the Norwegian physician are often more exaggerated in advanced cases8. and biochemist Ivar Asbjorn Folling in 193412. Shuttleworth saw “feeble mindness” as re- Penrose coined the name phenylketonuria and flecting a complex mixture of inherited and ac- demonstrated, thanks to the data collected by the 3609 Ciência & Saúde Coletiva, 24(10):3607-3617, 2019

Colchester Survey, that it was a hereditary reces- digestive anomalies while others did not have sive disorder13,14. PKU was presented by Penrose such anomalies; some had very severe intellectu- as a rare case of heredity of a mental impairment, al limitations while others, especially when they and, at the same time, a strong argument against received well-adapted and compassionate educa- eugenicists’ claims. He had calculated that about tion (contrary to received ideas, already in the 19th 1% of the British people are carriers of the PKU century selected institutions and educations pro- trait. It was pointless to try to control the repro- vided such education) made important progress, duction of all the individuals with this trait, while and some were able to live quasi-autonomous controlling only the affected people (assuming lives and hold jobs. that they will have offspring in spite of their se- Researchers rapidly arrived to the conclu- vere mental impairment) would have practically sion that “mongolism” in all probability a shared no effect on the frequency of the “defective” gene biological basis, but also that it does not run in in Britain, and would not prevent the birth of families. Children with this condition were near- children with the targeted condition. Only a lu- ly always born to non - affected parents, and had natic, Penrose concluded, would wish to sterilize non-affected siblings. In the 1930s, Lionel Penrose 1% of the population to prevent the birth of a had shown a strong link between maternal (but handful of harmless imbeciles15,16. not paternal) age and woman’s probability to have a child with “mongolism”. His hypothesis Aneuploidies and the rise of “genetic was that this condition is product of a joint effect conditions” of genetic predisposition and unknown factors linked with the mother’s advanced reproductive In the 1940s and 50s, significant portion of age. Another expert on “mongolism” Clemens experts believed that while a small number of Benda (1898-1975), an Austrian physician who diseases such as PKU or hemophilia correspond worked in the US, rejected Penrose’s hypothesis to the description of “pure” hereditary conditions and argued that “mongolism” is a metabolic dis- that obey Mendel’s laws, the majority of pathol- order produced by hormonal dysfunction. Such ogies described as “hereditary” are produced by a dysfunction is more pronounced in women multilevel interactions between heredity and over 40, but can be found in younger women too, environment. This view became however more because many children with “mongolism” were complex after 1959, following the description of born to young mothers19. the consequences of the presence of abnormal The understanding of “mongolism” – or as it number of chromosomes (aneuploidy) – and was renamed in the 1960s, Down syndrome – had the rise of an important new category of diseas- radically changed in 1959, when this condition es which were “genetic” but not “hereditary”. The was redefined as presence of abnormal number condition that played a key role in the transfor- of chromosomes. Normal human cells contain mation of understanding of “genetic diseases” 23 pairs of chromosomes. Each pair is composed was Down syndrome. from one chromosome originated from the moth- Down syndrome was seen for a long time as er, and another from the father, with the excep- puzzling phenomenon. Researchers who studied tion of sex chromosomes: biological women have children and adults with this conditions, noted a two x chromosomes, one from each parent (chro- surprising similarity of their physical traits; hence mosomal formula 46,XX) and biological men the early, racist, designation of people with this have a X chromosome inherited from their moth- condition as individuals with “mongoloid idiocy” er and Y chromosome inherited from their father or “mongols”. “Mongolism” was first designated (chromosomal formula 46,XY). The gametes (egg as a distinct entity by the physician John Lang- and sperm cells) contain 23 chromosomes each. don Down (1828-1896), a superintendent of the People with x Down syndrome have three, instead Earlswood Asylum for Idiots, in Surrey, England. of two copies of chromosome 21 (trisomy 21). In In an article published in 1866, Down described the great majority of cases (the sole exception are a “Mongolian type of idiocy.” In the late 19th and rare cases translocation of a segment of chromo- early 20th century physicians stressed the homo- some 21 on another chromosome) the presence geneity of facial traits of people with “mongoloid of three copies of chromosome is the result of an idiocy”17,18. At the same time they noted that such error of production of gametes, not a condition physiognomic similarity masked a great variety that occurs in families. of physical and intellectual manifestations. Some Until 1956, scientists did not have a reliable “mongoloid” children were born with heart or method to visualize human chromosomes, and 3610 Löwy I

they mistakenly believed that all human cells tion of studies of chromosomes revolutionized have 48 chromosomes. In 1956, two research- human genetics, but also medicine. Physicians ers, the Indonesian-American cytogeneticist, Joe had grasped that clinical genetics is as import- Hin Tjio, and the Swedish geneticist Albert Le- ant to the understanding of human pathology as van, developed a new method of staining human anatomy and physiology. Description of clinical chromosomes and had shown that humans cells consequences of presence of an abnormal num- have 46 chromosomes20. The development of an ber of chromosomes led to a distinction between efficient method of visualization and counting of inborn conditions defined as “genetic,” since they human chromosomes made in turn possible the were produced by changes in the genetic material study of aneuploidies (presence of an abnormal of the fertilized egg, and present in every single number of chromosomes). 1959 was named the cell of the body and those defined as “hereditary” “miracle year” of human cytogenetics – a disci- because they were transmitted from one or both pline which studies genetic changes on the level parents30. of cells21. That year three researchers from the In the early 1960s, cytogeneticists were able to Necker Hospital, Paris, Raymond Turpin, Marthe diagnose chromosomal anomalies in individuals Gautier and Jerome Lejeune, found out that with impairments produced by these anomalies, “mongolism” was correlated with the presence of while biochemists were able to diagnose heredi- three copies of the chromosome 2122,23. The same tary conditions such as metabolic diseases, often year a British group: the geneticist Charles Ford produced by a lack of an essential enzyme, by dis- from the Medical Research Council’s (MRC) Ra- playing the absence of this enzyme in cells of the diobiology Unit at Harwell, the physician and ge- affected individuals. It was not possible, however, neticist Paul Polani from Guy Hospital, London, to detect these conditions before birth. In 1968, and their collaborators, linked Turner syndrome Henry Nadler from Northwestern University – a condition characterized, among other things, Medical School, Chicago, developed a method by the under-development of sex glands in girls of cultivating fetal cells suspended in the amni- – with an absence of one X chromosome (chro- otic liquid. It was possible to sample these cells mosomal formula 45,0X) while Patricia Jacobs through the insertion of a needle into the am- and her group from the Medical Research Coun- niotic cavity of a pregnant woman (amniocen- cil Human Genetics Unit at the Western General tesis)31,32. In the early 1970s, amniocentesis was a Hospital in Edinburgh, linked Klinefelter syn- risky technique, linked with an estimated 5% risk drome a condition characterized, among other of miscarriage. On the other hand, it made possi- things, by the under-development of sex glands ble a prenatal diagnosis of severe hereditary dis- in boys, with the presence of a supplementary X eases as Nieman-Pick disease, maple syrup urine chromosome (chromosomal formula 47,XXY)21. disease, Tay Sach’s disease, or mucopolysaccha- The following year the geneticist Paul Edwards ridoses33,34. Previously many women who had af- from the University of Birmingham, UK, de- fected children refrained from a further pregnan- scribed the trisomy18 (Edward’s syndrome) and cy, because they knew that they had 50% chances Klaus Patau from the University of Wisconsin in to have another child with the same condition if Madison (USA) trisomy 13 (Patau’s syndrome) – it was dominant, and 25% chances if it was re- these two syndromes produce very severe inborn cessive. The liberalization of abortion in many anomalies24,25. These findings opened a new era Western countries in late 1960s and early 1970s of studies of inborn genetic conditions. allowed these women to test early in pregnancy whether the fetus was a mutation carrier, and Hereditary diseases, genetic conditions if that was the case, to terminate the pregnan- and prenatal diagnosis cy. Unsurprisingly, many among them strong- ly supported an approach that allowed them to Description of the links between inborn de- have children free of a “family malediction”, and fects and the presence of an abnormal number were willing to risk a spontaneous miscarriage to of chromosomes provided a powerful boost for achieve this goal. the development of medical genetics, previously In parallel, the possibility to culture fetal cells a marginal domain of studies26-28. As the Cana- in a test tube opened the way to a prenatal de- dian geneticist Clarke Frazer, explained: “genes tection of chromosomal anomalies such as Down were interesting hypotheses but here was a cause syndrome35,36. At first, since amniocentesis was a of genetic diseases that physicians could actually risky procedure, it was not proposed to women see”29. The scientific uses and practical applica- of “advanced maternal age” at higher risk of giv- 3611 Ciência & Saúde Coletiva, 24(10):3607-3617, 2019

ing birth to a child with Down syndrome37. In anomalies became the first cause of such mor- the late 1970s, the introduction of ultrasound to tality, increasing the physicians’ interest in this visualize the trajectory of the needle employed subject46. The description, in 1941, of severe birth to aspire the amniotic fluid reduced the risk of defects produced by an infection with rubella post-amniocentesis miscarriage to 1% envi- virus, then, following the explosion of atomic rons38. This technical improvement favored the bombs in Hiroshima and Nagasaki, the role of introduction of testing for an age -related Down radiation in producing inborn anomalies, were risk39,40. Gynecologists at first proposed this test additional sources of interest in such anomalies. only to women over 40, then over 38, and final- However, until the 1960s, birth defects were seen ly over 3541. In the late 1970s, prenatal tests for as a relatively minor domain of medical research. presence of hereditary diseases and abnormal One of the pioneers of study of teratology number of chromosomes were performed in the (literarily, the study of monsters) was the pedi- same laboratories by the same specialists. Yet, atrician Joseph Warkany (1902-1992)47,48. Born they addressed very different risks. Women who and educated in Vienna, Warkany moved in 1932 knew that they and/or their partner were carri- to Children’s Hospital in Cincinnati, Ohio, where ers of a hereditary condition had either 50% or he worked for the rest of his life. Warkany’s in- 25% probability to give birth to an affected child. terest in birth defects was rooted in his studies Women of “advanced maternal age” had a much on the effects of vitamin D deficiency, and in lower risk (1-3% according to age) to give birth his familiarity with cretinism (a congenital de- to a child with Down syndrome. Moreover, many ficiency of thyroid hormones), a condition fre- among these women were not aware of their risk, quently found in the Austrian Alps. In the 1940s and had to learn about it either from health pro- and 50s, Warkany and his colleagues conducted fessionals or the media. The Lancet’s editorial studied the effects of nutrition in pregnancy, and from 1977 stated that in the last five or six years in investigated possible causes of prematurity and Europe, only 300 abnormal fetuses were aborted low birth weight. Thanks to their efforts, tera- following a diagnosis of a chromosomal anoma- tology became a recognized, although modest, ly of the fetus, a very modest dent in the annual medical sub-specialty. The interest in teratology total of about 100,000 babies with such anomaly increased in the 1960s as a consequence of the born in Western Europe during that period. The thalidomide disaster, an epidemic of severe birth editorial recommended a vigorous campaign to defect in children of mothers who took a popular educate women about links between maternal anti-nausea drug, thalidomide, early in pregnan- age and Down syndrome42. Such educational cy. The striking images of “thalidomide children” effects were successful; in the early 1980s, more born without upper or lower limbs or both, at- women became aware of age-related risks, and tracted attention to risk of malformations during some explicitly demanded an amniocentesis43. pregnancy. It led to development of birth defect The detection of Down syndrome – an inborn registries, and epidemiological studies of causes impairment which is much more frequent than of anomalies in newborns. hereditary metabolic diseases and hereditary dis- In the 1960s and 70s the US pediatrician, eases of the blood – became the main target of David Smith (1926-1981), played a key role in search for genetic anomalies of the fetus and later systematization of study of inborn impairments. for population-based screening for such condi- In the early 1960s Smith collaborated with the tions44,45. geneticist Klaus Patau, who studied chromosom- al anomalies and described trisomy 13. Smith’s Abnormal development and abnormal main interest was, however, not genetic but fetal genes development (embryogenesis). Smith explained that chromosomal anomalies such as Down In the first half of the twentieth century, the syndrome were “internal dysmorphogenic in- main causes of newborns, babies and young fluences,” while infections such as rubella, and children mortality were infectious diseases and maternal factors such as severe diabetes or a mal- childbirth related problems. Extension and im- formation of the uterus, were “external dysmor- provement of the safety of hospital births, the phogenic influences.” In many cases a malforma- development of antibiotics, and the generaliza- tion produced by external cause was similar to tion of childhood vaccination, greatly reduced the one produced by internal one. For example, newborn and child mortality in industrialized cleft palate can be the result of a genetic anom- countries. After the Second World War, inborn aly or a faulty growth of the embryo produced 3612 Löwy I

by maternal factors. Moreover, the distinction oped a new staining technique – banding – that between external “maternal factors” and inter- was able to distinguish parts of chromosomes, nal “genetic factors” is far from being absolute. and see whether the chromosome is missing Maternal factors can modulate gene expression one segment (deletion), has one segment twice and contribute to the variability of phenotypical (duplication) or has a segment from a different profiles produced by a mutation. Smith’s view of chromosome (translocation). At first the band- dysmorphology was decidedly oriented toward a ing technique made it possible to identify a small multi-factorial understanding of developmental number of chromosomal anomalies. In the late delays and an integrated view of human embryo- 1970s and early 1980s the perfection of this tech- genesis which did not privilege genetic factors nique – more than 1000 bands were identified over others49. on human chromosomes – made possible the In 1966 Smith coined the term ‘dysmorphol- identification of smaller changes in the chromo- ogy” to replace the emotionally loaded term ter- some’s structure, and greatly expanded the num- atology and facilitate communication with par- ber of detected chromosomal anomalies53. The ents of children with inborn impairments50. In perfection of the banding technology opened an 1970 he published a highly influential textbook, era of intensive cytogenetic studies. Such studies Recognizable Patterns of Human Malformation: were extended to fetal cells too. The term muta- Genetic, Embryonic and Clinical Aspects51. This tion, previously applied to “Mendelian” diseases book rapidly became a reference volume for pe- produced by changes in a single gene, became in- diatricians, clinical geneticists and ultrasound creasingly associated with “syndromes,” a group experts who dealt with the expression of inborn of anomalies related to changes in chromosome’s defects. Consecutive editions of Smith’s Recog- structure. Syndromes such as Prader Willi/ An- nizable Patterns (Smith died in 1981, but his col- gleman syndrome, Cri de Chat syndrome or Wil- league and friend Kenneth Jones continued to liams syndrome often involve changes in numer- publish new versions of this book; the 7th edition ous genes associated with missing or duplicated was published in 2013) illustrate the evolution part of a chromosome. Syndromes tend to be of dysmorphology. Such evolution is reflected in associated with a large number of impairments the steady growth in the books’ size (the first edi- and are frequently, although not always, linked tion had 368 pages, and the 7th, 989) but also the with developmental delays and the presence of rapid increase in number of inborn syndromes abnormal (dysmorphic) traits54. linked to changes in the genetic material of the From the 1980s on, a DNA-based technology, cell. In the first, 1970 edition of this book only fluorescence in situ hybridization (FISH), made a small fraction of the described inborn malfor- possible a more refined analysis of chromosomal mations, mainly aneuploidies, were attributed to anomalies. FISH looks for the presence of specif- known genetic causes. In the, 7th edition of this ic – and known – anomaly in the cell. Segments book, 80% of the catalogued malformations were of DNA (probes) carrying the genes one is look- linked with identified genetic anomalies52. That ing for, are marked with a fluorescent stain. The edition included for the first time a separated probe is then mixed (hybridized) with fixed (in chapter on “molecular syndromes,” diagnosed situ), denatured chromosomes (chromosomes thanks to the development of new molecular bi- with an opened helix structure) of the tested cell, ology methods such as fluorescent hybridization and is allowed to attach to its complementary se- in situ and genomic hybridization. The rapid quence. The presence of a hybridized fluorescent diffusion of these technologies, especially in the probe – that is, the existence of a complementary 21st century, accelerated the process of “genetici- sequence on the tested DNA – is then revealed zation” of inborn pathologies. under light that excites the fluorescent dye. Flu- orescence is visible to the naked eye or measured Genetic diseases in the genomic era with specialized instruments. FISH and akin ap- proaches are used when physicians have a rela- The first cytogeneticists counted human tively precise idea of what the mutated genes they chromosomes. The usual technique was to stain are looking for are, either because they are pres- the chromosomes using some variant of Levan’s ent in the family, or because a clinical observa- and Tjio’s technique, photograph them, and tion, such as visualization of a skeletal anomaly then cut the photograph, and pair the chromo- in a child or a fetus, points to the direction of a somes, to check whether indeed there are two of specific condition. each pair. In the early 1970s cytogenetics devel- When physicians suspect that a patient has 3613 Ciência & Saúde Coletiva, 24(10):3607-3617, 2019

a genetic anomaly but do not know what this curacy, although experts strongly recommend anomaly may be, or, alternatively, they had made to confirm a positive result though amniocen- a tentative diagnosis but a genetic test disproved tesis. Before the advent of NITP, physicians had it, they frequently apply a different approach, access to fetal genetic material only through a comparative genomic hybridization (CGH). sampling of fetal cells, usually through amnio- CGH (also called chromosomal microarrays) is centesis, a stressful and still a risky procedure. an extension of FISH technology to the study of With the development of commercial NIPT, the whole genome of a cell. DNA from the tested they obtained such access – although as for now sample is labeled with a red fluorescent dye, while (2018) restricted to limited number of mutations DNA from a reference sample is labeled with a – through a simple blood test performed early green dye. The two samples are then mixed and in pregnancy. This technology allows therefore the observers measure the ratio of red to green a risk-free screening of all the pregnant women fluorescence at each chromosome. Deviations of for the presence of chromosomal anomalies. In the expected 1:1 ratio indicate the presence of many Western European countries in which this the anomaly in the tested DNA. The test, initially test is gradually integrated into monitoring of used in the same way FISH was and destined to pregnancy covered by a national health insur- the study of isolated cells, was made much more ance, NIPT is proposed (in 2018) only to wom- efficient through the use of fragments of DNA en defined as being at higher than usual risk of printed on a chip (microarrays), an approach having a child with one of the autosomal triso- that makes possible a very rapid comparison be- my, 21, 13 or 18. In countries, such as the US or tween DNA sequences. Brazil, in which NIPT is distributed through free FISH and CGH are complementary technolo- market (and may, or may not be reimbursed by gies. FISH answers the question, “Is the mutation the pregnant woman’s health insurance) this test X present in this patient?” CGH answers a differ- is often employed by low risk women who want ent question: “Is the patient’s genome normal?” a rapid confirmation that the “baby is all right.” and if an anomaly is found, indicates where it is Moreover, many of these women chose the “ex- located. GGH is especially useful for the search tended” version of NIPT, that looks not only for of chromosomal anomalies such as deletions, du- three copies of chromosomes 21, 13 and 18, but plications and translocations. When, following a also for sex chromosome anomalies (Klinefelter, display of a structural anomaly by CGH geneti- Turner, XXX, XYY) and the presence of selected cists suspect the presence of an already identified chromosomal deletions or duplications. Testing mutation, they can use FISH to confirm that this for the latter conditions may produce new dilem- indeed is the case. Taken together, these technol- mas for pregnant women. The case of DiGeorge ogies greatly extended the number of mutations syndrome, illustrates such dilemmas. linked with human impairments, and increased DiGeorge syndrome is produced by a deletion the perception a growing number of conditions, of a part of chromosome 22 (22q11del). It is a rel- such as autism, as “genetic”55. They also proposed atively frequent anomaly; its estimated frequency new, genetic, explanations of pathological phe- is 1 in 2000 live births (the estimated frequency of nomena. For example, physicians knew that chil- Down syndrome in industrialized countries is 1 dren with born with heart anomalies may display to 700 live births). DiGeorge syndrome is linked developmental delays as well, but they viewed with numerous physical defects, mild to moder- such delays as a secondary effect of a heart de- ate cognitive impairments (the mean IQ of peo- fect that might have perturbed the circulation of ple with Di George system is in the low 70s, but blood to the brain. Recent genetic studies pro- approximately 30% are in the normal range of 80 posed a very different explanation: heart anom- to 100) and high occurrence of psychiatric disor- aly and intellectual impairment are produced at ders, above all schizophrenia57. Scientists estimate the same time by the same mutation56. that 30% of cases of Di George syndrome are From 2012, a new technology, non-invasive transmitted in families as a dominant mutation prenatal testing (NIPT) grounded in the analysis (that is, can be defined as “hereditary”), and 70% of circulating free fetal DNA (cfDNA) in mater- are new mutations (that is, can be defined as “ge- nal circulation made possible to verify whether netic”)58,59. Experts stress the importance of mul- the fetus carries an abnormal number of chro- tidisciplinary management of this complex con- mosomes or displays chromosomal anomalies dition. Children with Di George syndrome suffer by examining fetal DNA present in the pregnant from feeding difficulties, infections, and many woman’s blood. The test has a high degree of ac- need surgeries for congenital heart and pharynx 3614 Löwy I

anomalies. In later life, people with this syndrome showing that the child’s difficulties were not pro- have difficulties with long – term communica- duced by something they did, allows to predict tion, and have learning, behavioral and mental the child’s future, and indicates appropriate med- problems: many of their symptoms correspond to ical, educational and psychological interventions. the definition of autistic spectrum disorders60,61. Is can also favor contacts between people affected The great majority of adolescents and adults with by a given condition and promote solidarity and this condition need some kind of educational and a disease-centered activism64,65. If the condition is psychiatric support, as do the great majority of “genetic”, that is, is the result of a new mutation, their caretakers, nearly always their parents. Nu- its diagnosis does not involve, however, decisions merous adults with DiGeorge are in psychiatric about reproduction. If the condition is “heredi- care62. Others live “normal” lives, and some never tary” and is transmitted in families, people who learned about their mutation. learn that they or their partners are mutation Reproductive guidance of people with Di carriers may however face complex reproductive George syndrome is a challenging problem. Peo- decisions. The nature of such decisions depends ple diagnosed with this syndrome following its often on the ways a given condition is concep- diagnosis in their child or in a fetus, have nearly tualized and framed. The finding that a disease always a milder form of this condition. On the is transmitted in families may or may not be the other hand, since DiGeorge syndrome has a vari- determinant element in the way people perceive able expression, it is impossible to predict the it. The practical consequences of the definition severity of pathological manifestation in a child of a given pathology as “hereditary” may depend of a person with mild variant of this syndrome. on its history, the pattern of its management by Before the advent of CGH, a prenatal diagnosis the medical profession, the nature of its mani- of DiGeorge was grounded in the observation festations, and sometimes on existence or not of of morphological anomalies, such as heart and active association of patients that puts to the fore palate defects. The growing use of CGH to study its hereditary aspect. miscarried or aborted fetuses enlarged the num- Some “older” hereditary diseases such as he- ber of anomalies linked with DiGeorge syndrome mophilia or sickle cell anemia were historically because in many cases the study of genetic mate- defined as transmitted in families. Other diseas- rial of a miscarried or aborted fetus that was not es, such as Tay Sachs disease (a metabolic disease initially suspected to have a DiGeorge syndrome invariably fatal at a young age), or thalassemia revealed a deletion of a part of chromosome 2263. (a blood disorder which today is not incompat- With the lowering of costs of molecular biolo- ible with life but often produces a severe impair- gy tests, search for DiGeorge syndrome became ment), became strongly identified as “hereditary” a part of a routine investigation of structural through mass campaigns that aimed at their anomalies of the fetus revealed by obstetrical ul- elimination such as the efforts to eliminate Tay trasound. It is further extended in countries in Sachs disease among Ashkenazi Jews, or efforts to which many pregnant women undergo “extend- reduce the prevalence of thalassemia in Cyprus ed” NIPT testing. These women, the majority of or Iran36,66-68. In Israel, the ministry of health is which probably had never heard about DiGeorge actively promoting the identification of the carri- syndrome, may learn that their future child may ers of hereditary diseases such as Tay Sachs, cystic face challenging physical cognitive and psychiat- fibrosis or familiar dysautonomia with an explicit ric problems. They may also learn that this child aim of preventing the birth of children with these may have only mild physical and mental disabili- conditions through a combination of pre-con- ties and may lead a “normal life”, which, if s/he is ceptional diagnosis that in some cases may lead lucky, will be unburdened by knowledge of being to a couple’s decision not to marry or not to have a mutation carrier. biological children, early prenatal diagnosis cou- pled with a selective abortion and, more recently Life with – or without – genetic diagnosis also pre-implantatory diagnosis – in vitro fertil- ization followed by a diagnosis of disease – linked A diagnosis of a genetic disease – often made mutation in embryos, and implantation of em- in an affected child – may be very important, bryos devoid of this mutation69,70. even – as alas, it is frequently the case – it does Other diseases, although clearly without any not lead to a cure. An accurate diagnosis can pro- doubt resulting from a mutation transmitted in vide an explanation of the difficulties encoun- families have a more fluid status. Phenylketon- tered by this child, reduces parents’ culpability by uria (PKU) is a hereditary recessive condition, 3615 Ciência & Saúde Coletiva, 24(10):3607-3617, 2019

but since it is considered curable / preventable from the Réunion island, who resisted the diag- through the maintenance of low phenyl alanyl nosis of a genetic disease (limb-girdle muscular diet, its hereditary dimension is often minimal- dystrophy- LGMD) that runs is its family, and ized16. Conditions such as polycystic kidney dis- did not seem concerned by risk inheritance of ease (in the majority of the cases, a dominant this disease by his children and grandchildren. hereditary disorder) and heterochromatosis (a While Gino’s brother, Leon, was very active in recessive hereditary disorder) are seen main- the muscular dystrophy association of Réunion, ly as “diseases,” not mainly as “hereditary.” The Gino refused all contacts with this association. weak focus on their transmission in families His passive but obstinate resistance to enter the is probably related to the fact that they have a biomedical space in which he is defined as a car- highly variable expression (some people who rier of “faulty” gene, allowed him to reject a defi- inherit the disease-related gene are sick, while nition of “genetic kinship” imposed from outside, others are healthy), great differences in the time and the moral decisions an entrance into this of appearance of symptoms in affected people network will automatically entail. By refusing ge- and the severity of the symptoms, and the exis- netic testing, Gino kept his freedom to define the tence of an efficient therapy. People with poly- kind of bonds between people that are important cystic kidney disease and heterochromatosis are for him. When he rejected his brother pleas to get often more concerned about getting the right tested whether he carried the LGMD gene, and diagnosis and an adequate treatment for their explained that he “does not want to know,” Gino symptoms – if they develop them at all – than affirmed his right to be himself, not the person about the transmission of a hereditary trait to others want him to be73. offspring71,72. Moreover, these pathologies are Today’s industrialized societies – and increas- not seen as belonging mainly to the jurisdiction ingly also those of “intermediary” and developing of geneticists, but to the domain other medical countries – are dominated by biomedical ratio- specialties, respectively nephrologists and hema- nality. Yet, people are still free to either elect to live tologists. These specialists tend to be more con- in diagnosis and in prognosis or to live elsewhere. cerned about diagnosis and care of an already They can chose to what degree their diagnosis de- existing condition than about its inheritance. fine what essentially they are at a given moment Finally when a predominant understanding of of their life. Even those diagnosed with a lethal an inborn condition is not shaped by a powerful condition still can elect to see themselves above disease-focused organization – which do not ex- all as “waking dead,” as being alive– or both74. ist for polycystic kidney disease and heterochro- As the historian of medicine Charles Rosenberg matosis – affected people and their families may explained, diagnosis and prognosis do not deter- have more possibilities to construct their own mine the ways individuals deal with them. Diseas- narratives about the meaning of life with this es Rosenberg proposes, “are stages on which we condition. Such narratives may include the rejec- perform as individuals and as moral actors. In the tion of the label “hereditary.” West’s bureaucratic and technology- dependent The sociologists Michel Callon and Vololona environment, it is ironic that in some ways pain, Rhaberisoa followed the story of a patient, Gino, sickness, and incapacity remain a final and ulti- mately inaccessible citadel of individuality. We are shaped by our diagnoses, but we are not reduced to them”75. Genes are (still?) not us. 3616 Löwy I

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