Medical Genetics:The New Preventive Medicine

Number 36

Recently, I published an essay de-scribing the current state of preventivemedicine and the impressive efforts be-ing made by the Centers for DiseaseControl (CDC) to incorporate this phi-losophy into standard medicalpractice. 1 Shortly after that essay waspublished, I received a letter fromcytogeneticist D. Soudek, KingstonPsychiatric Hospital, Kingston, On-tario, pointing out I had failed to discussa very important aspect of preventivemedicine—medical genetics. z In fact, Iwas somewhat stunned by this impor-tant reminder as I had been planning anessay on medical genetics for sometime. Considering ISF’s early work indeveloping a citation index to thegenetics literature, it is somewhatdisconcerting to realize how littleeditorial attention I’ve devoted to anyaspect of genetics. Soudek’s letter mere-ly emphasizes that even knowledgeablepeople do not automatically think ofmedical genetics as an important part ofpreventive medicine-if not now, cer-tainly in the future.

Until recently, physician involvementin what is now being called medicalgenetics was largely confined to discuss-ing the recurrence of genetic disordersand explaining the limited number ofoptions available for preventing thebirth of a child with these disorders.Since, for many years, most geneticdiseases could only be detected after thebirth of a child, medical genetics was

September 7,1981

mainly the province of physicians andresearchers investigating “esoteric”diseases known to have a genetic com-ponent. One exception to this general-ization was the discovery that differentRh blood groups in parents can pose athreat to their offspring. Blood tests todetect this hereditary incompatibilityhave been available for many years.

In the past 20 years, new and moreaccurate methods of diagnosing heredi-tary disease have been developed.Researchers have also recognized thatmany diseases that occur later in life aregenetically influenced. As a result,physicians and basic research scientistsalike have increasingly focused their at-tention on the genetic basis for disease.In addition, each year thousands of per-sons are requesting amniocentesis andother medical techniques which candetect specific diseases in the fetus.People are requesting these testsbecause they have a family history ofhereditary diseases, are concernedabout having a defective child, or areconcerned about having a child withchromosomal abnormalities related tothe parent’s advanced age.

More than 3,000 diseases are knownto have a genetic component, and 150new ones are being recognized eachyear, according to James R. McBee, di-rector, National Clearinghouse for Hu-man Genetic Disease, which pro tidesinformation on genetic screening andtreatment programs. J So the preventive

222

value of recognizing the presence of, orsusceptibihty to, genetic disease can befar-reaching.

Methods for prenatally diagnosinggenetic disease have helped to diminishthe fears of people who might not havechosen to become parents without theknowledge now available. In a sirnifarvein, individuals with a hereditarysusceptibilhy to certain diseases cannow take steps to moderate the diseaseor begin treatment in its early stages.

Whife knowledge of inherited factorsin disease has been available since theearly 1900s, it generally was not appliedto clinical practice until the 1950s.4 Partof this delay can be attributed to theearly affiliations of some medical“hygienists)’q with the already well-established eugenics movement. Scien-tists in Europe and the US were doingresearch on the hereditary transmissionof human traits prior to the twentiethcentury, but institutions devoted topredicting the recurrence of inheritedhuman diseases originated in the US andUK. As is well-known, in Germany—where eugenics research and publica-tion were quite active around the turnof the century-eugenics became apolitical issue, despite the best inten-tions of many geneticists.

Two of the major institutions in theUS and UK where genetics was first ap-pfied to human health were also associ-ated with the controversial field of ap-plied eugenics. The Laboratory of Na-tional Eugenics, established in Londonin 190’7, was closely aligned with thebeliefs of its founder, Francis Galton. 5.6

He is well-known for KIS advocacy ofselective human breeding.

Charles B. Davenport, who estab-lished the frst institute for humangenetics in the US, tried to show thatcriminality and insanity representedsimple Mendelian traits. 7 The EugenicsRecords Office was founded by Daven-port in Cold Spring Harbor, New York,in 1910.6 This was only ten years after

the rediscovery of the work of GregorJohann Mendel, the nineteenth-centurymonk who elucidated the fwst laws ofheredity. Mendel theorized that thetraits observed in pea plants occurredthrough generations because of pairedelementary units of heredity. Thesewere later to be cafled genes. Heworked out the statistical occurrence ofthese traits and, although furtherrefinements and elaborations to his lawshave been made, they stifl form thefoundation of modem genetics. There isa considerable mythology about thelong delay in the acceptance of hisideas.8,g

In the early 1900s, then, humangenetics was often treated as that part ofeugenics “concerned with the acquisi-tion of knowledge of human heredity.”bIn many cases, this happened becauseboth subjects were taught by the sameperson at universities and cofleges.

Although many geneticists dld not in-vestigate medical genetics because of itsassociation with eugenics, an even moreimportant factor was the difficulty ofstudying the hereditary transmission ofdiseases and traits in humans. As is so>ften the case, scientists who were in-terested in human genetics did not have[he technical methodology to study he-reditary disease in man.

While the eugenics movement andmethodological limitations may explain~ general lack of interest in medical;enetics among genetics researchers, itioes not explain why physicians took soong to adopt Mendelian thinking intoheir practice and research. The reason

‘or this is the same as for their lack of in-erest in preventive medicine. Accord-ng to A. CapIan, Hastings Center, Has-:ings-on-Hudson, New York, they sim-)Iy were not aware of its relevance. Dur-

ng the early part of this century, physi-cians infrequently came across diseaseshat showed Mendelian inheritance pat-ems. And diseases which showed such)attems were frequently untreatable.

223

Consequently, physicians didn’t believethey were worth studying. 10Additional-ly, doctors and researchers were “busilyextending their new etiologic model ofdisease,”lo Medical attention at thispoint was focused on microbial sourcesof disease and infection.

As a result of these factors, geneticsremained primarily the territory of zool-ogists and botanists until the 1950s. Atthis point, the control of nongeneticdiseases—those caused by infection andnutritional deficiency—was advancing,so that attention could focus more ongenetic disease.4 The number ofdiseases recognized as displaying Men-delian inheritance patterns also beganto increase. Medical geneticists werenow able to make estimates of the risksof recurrence of hereditary disease.

According to F. Clark Fraser, McGillUniversity, the next major “boost” tomedical genetics came with advances inmolecular and biochemical genetics,which led to the identification of “in-born errors of metabolism.”q Thk termwas first introduced by A,E. Garrod,Oxfotd University, who was also thefirst to describe Mendelian inheritancein human disease. II .12The term “inbornerror of metabolism” is now used to de-scribe any genetically determined bio-chemical disorder in which enzymaticdefects produce problems of metabo-lism. The discovery that one such en-zyme deficiency, which results in men-tal retardation (phenylketonuria), couldbe successfully treated had majorramifications.4 Infants in most states ofthe US and in the UK are now regularlyscreened for th~ defectl J and for con-genital hypothyroidisms

During the 1950s, a number of majordiscoveries further advanced our under-standing of medical genetics. In 1956,J.H. Tjio, Experimental Station ofAula, Zaragoza, Spain, and A. Levan,Institute of Genetics, Lund, Sweden; 14

and C.E. Ford and J.L. Hamerton,Medical Research Council, Berkshire,

England, 15independently demonstratedthat the number of chromosomes inman was 46, rather than the 48 previous-ly believed. The methods developed bythese scientists made possible the accu-rate study of human chromosomes.They also led to the recognition, in1959, that chromosomal irregularitiesare associated with a number of syn-dromes. ls-1~ Victor McKusick, JohnsHopkins University, explains that theseevents actually led to the birth of “clini-cal genetics” in that they “gave theclinical geneticist ‘his organ’ like thecardiologist has hk heart, the ophthal-mologist his eye and so on. ” He adds

that various biochemical methods de-veloped since the 1950s, and somaticcell hybridization, a technique in whichthe genetic information from two differ-ent types of cefls is combined, havehelped researchers further define genet-ically-based biochemical differences inhumans. 19

At present, physicians and scientistsuse tissue culturing and karyotyping todetect chromosomal abnormalities. Inthis type of chromosome analysis, cellsare allowed to divide in tissue culture.They are then arrested in metaphase,the stage of cell dhision during whichthe chromosomes are separated into ex-actly similar halves. The cells are thenstained and the chromosomes are eitherobserved under a microscope, and ab-normalities noted; or, a microphoto-graph of the chromosomes is taken andthe chromosomes arranged according toa standard classification system. ‘Ilk ar-rangement of the chromosomes is calleda karyotype. The karyotype is thenstudied for structural or numerical ir-regularities. A process cafled banding,in which the patterns of bands on thechromosomes are studied, enables sci-entists to observe, with great precision,mat erial that maybe present, absent, orirregularly located on the chromosome.Incidentally, the word karyotype shouldnot be confused with eukaryote or pro-

224

karyote, although these words are allderived from the Greek “karyo,” whichrefers to the nucleus of the cell.~ A pro-karyote is an organism—bacteria, forexample—that does not have a truenucleus, so that nuclear material is scat-tered in the cytoplasm of the cell. Aeukaryote has a true nucleus, boundedby a nuclear membrane.

More recently, with the developmentof diagnostic methods such as amnio-centesis, ultrasound, and radiologic ex-amination, it became possible to diag-nose chromosomal aberrations, certaininborn errors of metabolism, and othercongenital abnormalities in the fetus.

Amniocentesis,zl-~ the most widelyused method of prenatal diagnosis, is aprocess in which amniotic fluid is drawnfrom the womb during the fourteenth tosixteenth week of gestation and ana-lyzed for those diseases and chromo-somal abnormalities suspected in the fe-tus. The fluid itself is analyzed for neu-ral tube defects, and cells within the flu-id are cultured and anafyzed for manychromosomal abnormalities and morethan 100 inborn errors of metabolism.

The predominant application of am-niocentesis so far has been for detectionof Down syndrome (mongolism) in thefetuses of women 35 and over. Duringthis period the risk of giving birth to achild with a chromosomal disorder ap-preciably escalates. About 40 otherdisorders have been diagnosed throughamniocentesis, including Tay-Sachs dis-ease, a deficiency of brain lipid metabo-lism: galac[osemia, a biochemical defi-cienc y of carboh ydrate metabolism; andthalassemia, a hemolytic anemia causedby abnormal synthesis of hemoglobin. 24Amniocentesis is a fairly painless andsafe procedure. Its main risk, if any, is aless than one half of one percent chanceof inducing abortion. 25

Ultrasound, another method of pre-natal diagnosis, involves the passage ofhigh frequency sound through thewomb. This enables physicians to locatethe fetus and placenta,zb and is usualy

used in conjunction with amniocentesis.Ultrasound makes it possible to detectmultiple fetuses. By accurately locatingthe fetus and placenta, the physiciancan avoid fetal injury when drawing am-niotic fluid through a needle. Examina-tion of the fetal head through ultra-sound afso can help in the diagnosis ofanencephaly, the absence of a cranium,and other structural defects.

The most direct way of examining thefetus is through a fetoscope, a tubewhich can enter the womb and be usedto remove a sample of fetal blood or tis-sue.27,z~ Disorders such as sickle cellanemia and thalassemia can be diag-nosed this way. Unfortunately, the feto-scope, which is still in the research stageof development, has an appreciable riskof fetal Ioss. Z4As a result, this method isinfrequently used.

Another method, amniography, orX-ray examination of the fetus, 29 is use-ful for finding disorders that are charac-terized by the absence, or gross struc-tural abnormality, of specific bones.~One such example is achondroplasia, atype of dwarfism, which can be recog-nized radiologically at between 20 and24 weeks of pregnancy. 19

Finally, a relatively new method ofdiagnosing neural tube defects, a classof malformations of the brain and spinalcord including anencephaly and spinsbifida, is the alpha-fetoprotein (AFP)test.31 Neural tube defects, which canlead to death, paralysis, and mentalretardation and occur somewhat ran-domly, can be prenatally detected byanalyzing the mother’s blood serum forlevels of alpha-fetoprotein. This proteinnormally rises in concentration in themother’s serum during pregnancy.Higher than normal quantities may in-dicate the presence of a neural tubedefect, multiple pregnancy, fetal death,or other defects. When found, this in-dicates a need for additional tests. Kitsfor this test, which could be used forwidespread screening, are currently be-ing evaluated by the US Food and Drug

225

Administration.Q Incidentally, theprimordial publication on the AFPtestsl was recently a Citation Chrsic. 33

Of course, most diagnostic testsreveal that the fetus is normal, whichcan relieve parents of the anxiety theymay have from suspecting it is defec-tive. When a defective fetus is detected,this knowledge—besides giving parentsthe choice of abortion-enables thephysician to begin treatment at birthand, in some cases, treat the fetus in thewomb.

Many of these diagnostic tests areused in conjunction with geneticcounseling. As defined by C.R. Striver,McGill University, genetic counseling is“a communication process that attemptsto help an individual or family to com-prehend medicaf facts, to appreciatehow heredhy contributes to the dkor-der, to understand the options for deal-ing with recurrence risks, to act uponthese options in a manner appropriatefor the counselee, and to make the bestpossible adjustment to the presence orrisk of the disorder in themselves, theiroffspring or other family members. ” 1I

The genetic counselor generally per-forms a complete medical review of theindividual’s pedigree, or family tree. Ifthere’s a possibilhy that the parents arecarriers of a hereditary disease ordeleterious genes, they are advised of alloptions, including predictive tests whenpossible. In many instances, geneticcounselig involves more than the pure-ly scientific prediction of recurrence ofhereditary disease. It may include help-ing the parents examine their attitudestoward having a defective child. Genet-ic counselors may afso provide informa-tion about the financial and emotionalaspects of raisiig such a chiid, and helpparents who already have a defectivechild cope with their situation,

Most of this counseling had beendone in the past by doctoral levelgeneticists. More recently, internists,pediatricians, and obstetricians withspecial knowledge of medical genetics

have offered genetic counseling. And atleast eight universities now offer pro-grams leading to either a master’sdegree in genetic counseling or amaster’s in social work, with a geneticcounseling specialt y.s These includeSarah Lawrence College; University ofCalifornia at Berkeley, Los Angeles,and Irvine; Howard University; Univer-sit y of Michigan School of Medicine;University of Pittsburgh; and Universityof Wisconsin-Madison. 3

No US certification has been offeredin this area in the past, but in Decem-ber, the recently established AmericanBoard of Medical Genetics will offercertification through a series of five ex-aminations. These exams, which will beadministered by the National Board ofMedical Examiners, will include a coreexam to be taken by all medical geneti-cists, a clinical geneticist exam to betaken by physicians and dentists, amedical geneticist exam for personswith doctorates, a clinicaf biochemicalgeneticist exam, a cliiical cytogeneticistexam, and an exam for genetic counsel-ors. Hope Punnett, a member of theAmerican Board of Medical Genetics,said the board hopes to offer an exam inctilcal immunogenetics in the future. ~The Canadian College of Medical Ge-neticists, which was incorporated in1975, has been certifying MD and PhDmedical geneticists for several years, 1I

Most people who consult geneticcounselors do so after already havinghad a child with a hereditary disease.Others are patients with a history ofgenetic disease they don’t want to passon.JS But many physicians advocate the

use of genetic counseling prior to mar-riage, Even simple knowledge about Rhfactors needs to be explained. In em-phasizing the preventive nature of medi-cal genetics, A. Mdunsky, Harvard Uni-versity, lists such options as carefulselectibn of a mate, determining if youare a carrier, prenatal testing, abortionof severely defective fetuses, artificialinsemination, and adoption. He also

226

recommends that individuals who sus-pect they are earners of a genetic dis-ease be screened for the dkease in ques-tion.~

Population screening for carriers ofgenetic diseases has been successfullyapplied to Tay-Sachs disease, an en-zyme deficiency carried by one in 30 USJews of Ashkenazic (East European) de-scent, and, to a lesser extent, to sickle

cell anemia, a blood dkease earned byone in ten Black Americans. Screeningfor thalassemia has been done in severalMediterranean countries and in parts ofthe US.~ Since genes for these diseasesoccur more frequently in these subpop-ulations, and fairly accurate tests areavailable for their detection, a wide-spread screening program can be cost-effective. But most genetic diseases oc-cur less frequently in larger populations,so the costs of routine populationscreening for those few d~eases whichcan be detected are less cost-effective.

Hereditary diseases can be passed onto progeny in a variety of ways. Mostdiseases are recessive, which means thata person must inherit a defective genefrom both parents in order to manifestthe d~ase associated with that gene. Ifboth parents are earners of the samegene, each chfid will have a 50 percentchance of being a carrier (carries thegene but does not have the dkease). Foreach child there is also a 25 percentchance of having the d~ease and a 25percent chance of not being a Carner orhaving the disease. Most forms of albi-nism, which affects the pigmentation ofthe skin, hair, and/or eyes, are reces-sive.~

With dominantly inhetited diseases,at least one parent has a gene thatdominates the counterpart, or “allele,”contributed by the other parent. In thiscase, each child of an affected individu-al has a 50 percent risk of inheriting thedisease. Certain dominantly inheriteddiseases may be expressed more severe-ly in one member of a family than in an-other. One such example is neurofibro-

matosis, a chsorder of the brain and ner-vous system in which some children mayhave mild and others severe symptoms.

Over 100 hereditary diseases areknown to be X-linked. These disordersresult from a defective gene on one ofthe X chromosomes. In X-linked inhen-tance, each of a female earner’s sonswill have a 50 percent chance of inherit-ing the X-liiked d~ease, and eachdaughter, a 50 percent chance of beinga carrier. If only the father has thedisease, the daughters wilf alf be carriersand the sons will not be affected. Final-ly, if the father has an X-linked diseaseand the mother is a carrier, there is a 50percent chance a daughter will be af-fected and a 50 percent chance she wiffbe a carrier. There is also a 50 percentchance a son will be affected. Manyforms of mental retardation are believedto be X-linked.~

Most X+mked genetic defects causeovert disease only in sons. Daughters re-ceive two X chromosomes, which maycounteract each other, but sons receiveonly one X, and a Y which does notcounteract the genetic disease carriedby the X. So determining that a fetus ismale is often the only way to find out ifthe mother is likely to have an affectedchdd. For example, if the mother is acarrier of the hemophilia gene, whichcauses d~ease only in males, each of hermale children wilf have a 50 percentchance of having the disease. Unf ortu-nately, only six X-linked diseases—Hunter syndrome, Fabry’s disease,Lesch-Nyhan syndrome, Menkes syn-drome, several forms of hemophilia,and chronic granulomatous dwase-can actually be detected in the fetusitseff. So mothers who are carriers ofother severely debilitating hereditarydisease genes may choose to abort allmale fetuses.~ This was formerly done,on occasion, with hemophilia, but newmethods of therapy are improving theprognosis in this disease and selectiveabortion of males is becoming question-able. Since there is no adequate ther-

227

spy, carriers of certain types of muscu-lar dystrophy genes sometimes elect toabort all male fetuses.

While some carriers of X-linkeddiseases may have mild manifestationsof the dkease, there may be some ad-vantage to being a earner, particularlyof a recessive dkease. In some in-stances, carriers may have increasedresistance to an unrelated disease. Forexample, carriers of the sickle cellanemia gene have greater resistance tomalaria. ~ %nilarly, individuals withDuffy negative blood group havegreater resistance to a certain type ofmalaria. 37

There are three basic types of geneticdisease. In Mendelian inheritance,which I discussed above, single genes orgene mutations are inherited in recog-nizable patterns. This accounts forabout 25 percent of genetic disease.Chromosomal aberrations, or an abnor-mal number of chromosomes caused bymutation or inheritance, account forabout 13 percent, and multifactorial orpolygenic inheritance, in which the in-teraction of genes and nongenetic (envi-ronmental) factors cause disease, ac-counts for about 44 percent. %

Despite the fact that about four per-cent of aU livebom children will havesome hereditary disorder, zd there areonly about 231 genetic counseling andscreening programs in the US3 and 843worldwide. BQThe lack of insurance pay-ment for genetic counseling has probably been a factor in the paucity of pro-grams. In fact, at least one studyshowed that the majority of patientswho come for counseling are in the mid-dle and upper income brackets.gs

When you consider that it costs atleast $250,000 for lifetime support of aperson with Down syndrome,~ thejustification for insurance payment forthese services becomes evident. Milun-sky emphasizes the price paid by par-ents who have not availed themselves ofgenetic services. “The presence of achdd with serious birth defects in the

home becomes a chrome emotional anaphysical drain on the parents, leadingoften to a severe state of exhaustion af-fecting all avenues of their life. Eco-nomic hardship may follow and ahnostinvariably increases marital conflict . . . .Separations and divorce are only toowell known in farnihes where suchtragedies have occurred. The enormousdrain on the energies of the parents fre-quently leads to a relative neglect of theunaffected children. ”m (p. 9)

Although the emphasis of medical ge-netics has been largely on birth defectsand prenatal screening, this is by nomeans the only field in which an under-standing of the genetic basis of diseasehas been applied. As I mentionedearlier, members of the biomedicalcommunity are investigating and, insome cases, applying their knowledge ofgenetics to hereditary diseases thatmanifest themselves later in Me.

While research on the genetic basisfor such dkeases is still fairly new, inves-tigators are beginning to emphasize theindividuality of each person’s geneticprofile. Striver and colleagues, indiscussing the evolution of medicalgenetics, explain that the geneticparadigm for disease “recognizes therole of intrinsic (genetic) factors for in-dividual homeostasis and susceptibilityor resistance to disease . . . . Because indi-viduals have their own geneticsignature, it follows from the geneticparadigm that each person is at his orher own specific risk for a particulardisease.”11

Coronary heart disease, for example,is often associated with high bloodlevels of cholesterol or triglycer-ide—conditions which are partiallydetermined by genetic factors. Onesuch condition, familial hypercholester-olemia, is transmitted through a domi-nant form of inheritance. It can betreated through reductions in the intakeof cholesterol and saturated fat. Thegene for this disease is carried by aboutone in every 500 individuals in the US. -~

228

Another disease, familial hypertri-glyceridenda, affects about one in every300 individuals in the US. In addition tocoronary disease, individuals withfamilial hypertriglyceridemia have ahigher frequency of diabetes and obesi-ty, and may be resistant to insulin.m

In familial combined hyperlipidemia,which affects nearly one in 200 in theUS, there is a high blood fat level thatcan cause heredhary disease. Finally, inpolygenic hypercholesterolemia, highblood cholesterol is caused by the inter-action of genes and environmental fac-tors. Other genetically related causes ofheart disease include hereditary defectsin the structure of the heart and hyper-tension.~

There is also evidence that cancermay have a hereditary component. Forexample, it has been found that womenwith breast cancer that occurs prior tomenopause often have affected rela-tives, particularly when the cancer oc-curs in both breasts. It has been sug-gested that some susceptible womenlack an enzyme (estradiol hydroxylase)that would normally process the estro-gen made by their ovanes.m Specificcancers have also been associated with anumber of chromosomal disorders, in-cluding Down syndrome and Klinefeltersyndrome,~ Addhionally, it is currentlybelieved that many malignant disordersoccur in genetically disposed individualsexposed to environmental carcinogens.A review article by Purtilo and col-leagues lists more than 240 tumors thatmay have a hereditary component, 40

Studies to assess the genetic com-ponents of disease often involve com-paring the behavior and disease patternsof identical and nonidentical twins.dl 42Since identical, or monozygotic, twinshave identical genetic profiles, a highconcordance rate bet ween them, ascompared to dizygotic twins or siblings,suggests a genetic basis for the condi-tion being considered. Researchers alsoconduct studies on adopted children inan effort to isolate the environmental

Iactors that might contnbute to disease.If a relationship can be made betweenthe illness of biological parents and thechild they’ve given up for adoption,genetic factors may be implicated.

In his review of genetic counseling forpsychiatric patients, M.T. Tsuang,University of Iowa, reports that insevere alcohol abuse a concordancerate of 84.5 percent was found betweenidentical twins, while the rate was 66.7percent for fraternal twins.ds He alsonotes that a Danish study of alcoholismamong adoptees and their parents founda much higher rate of alcoholism in thesons who had been adopted from alco-holic biological fathers than among con-trol adoptees. The rate was no higherfor daughters who had been adoptedfrom alcoholic fathers.

A number of other psychiatric disor-ders, including manic-depression, 44schizophrenia, and presenile dementia,dsalso are believed to have a genetic com-ponent. George Winokur, University ofIowa, is among many scientists whobelieve that bipolar, or manic-depres-sive, illness can be genetically transmit-ted. He afso suggests there is a geneticcomponent in unipolar, or depressive, ill-ness. Winokur estimates that the sibfingof a manicdepressive individual has a 26percent risk of being affected if oneparent is affected, and a 43 percent risk ifboth parents are affected.~

Not surprisingly, “ecogenetic” stud-ies—studies of genetic variation in sus-ceptibility to physical, chemical, andbiological environmental agents—areincreasing as new knowledge of geneticsbecomes available. 47 These studies areconcerned with many of the genetic dis-eases I’ve already discussed, particularlythose that can be considered muhifac-torial.

Many types of cancer are suspectedof being ecogenetic, since specific can-cers occur more frequently in certaingeographic areas. Researchers are ex-ploring the possibility that “geneticallydetermined differences in carcinogenic-

229

.,metabolizing enzymes affects suscepti-bility to various cancers. ‘“@Lactose in-tolerance~ is thought to be a recessiveecogenetic dkease, while the factorsthat determine whether or not caffeinewill keep you awake at night may begenetically determined.~

A subfield of ecogenetics, pharmaco-genetics, is concerned with hereditaryfactors that affect individual reactionsto drugs and chemicals, Pharmacoge-neticists emphasize the need to investi-gate each patient’s genetic susceptibilityto various drugs before they are ad-ministered and to tailor drug regimensto individual needs. Many hereditarycondhions, which by themselves causefew problems, are activated when theaffected individual is exposed to variousdrugs. A classic example is glucose-6-phosphate dehydrogenase deficiency,an inherited deficiency of an enzymewithin the red blood cell. This disorderoccurs most often among Orientals andBlacks. If a person with this deficiencytakes any of a number of drugs, in-cludlng aspirin, he or she may develop ahemolytic anemia, a condition in whichred blood cells are destroyed.~

Alcoholism is also the subject ofpharmacogenetic investigation. For ex-ample, Peter Propping, University ofHeidelberg, suggests that genetic fac-tors may influence an individual’s abilityto metabolize alcohol, as well as his orher tolerance of, and dependence on,this substance. A number of observa-tions support a genetic basis for suscep-tibility to alcoholism. They includevarying EEG patterns following alcoholconsumption and differing enzymaticreactions to alcohol among variouspopulations. Mongolian people, for ex-ample, respond to alcohol with rapid,intense flushing of the face and symp-toms of intoxication much faster thando most Caucasians. @

Exposure of genetically disposed indi-viduals to various chemicals is believedto cause cancer and other diseases. Anumber of chemicals, and ionizing radi-

ation, ~ are known to cause genetic mu-tations Ieadmg to disease, reduced fer-tilhy, and the birth of defective chil-dren. Researchers at several institu-tions, including the University of BritishColumbia, the Chalk River Nuclear Lab-oratories, Ontario, 51 and the Universityof Oslo, 52 are looking at how these mu-tated genes are carried by future gener-ations, and at the repair mechanisms ofthese genes.

The diseases that may be environ-mentally induced as a result of geneticpredisposition are too numerous toname here. However, a review of thesediseases makes it eminently clear thatmany political and social problems willarise before a fulf understanding ofgenetically determined disease has beenreached, Indkiduals susceptible to anyof the diseases that can be provoked byexposure to chemical substances may bebarred from jobs employing thesechemicals. Food additives known to in-duce disease in predisposed individualsmay have to be taken off the market.

Controversies and problems havealready surfaced from what is known (ornot known) about susceptibility todisease and about people who are car-riers of harrnf ul recessive genes. In theUS, several Black people were barredfrom the armed forces and asked to payhigher insurance premiums becausethey carried the sickle cell anemia gene.And in Greece, young women discov-ered to be carriers of thk trait foundthemselves ineligible for prearrangedmarriages. ~

Even more volatile arguments arecurrently under way concerning prenataldiagnosis, abortion, and genetic re-search. Questions arise about the rightto life of the defective fetus indepen-dent of the lifetime burden the handi-capped child will be for its parents andsociety. Several authors have suggestedthat illnesses that are prenatally diag-nosable but can’t be treated at presentmay be ignored by medical researchers.These authors imply that, since fetuses

230

with these defects can be detected andaborted, researchers wiff feel there is noneed to search for cures.

As Joshua Lederberg, president,Rockefeller University, points out,“Few subjects pose as many difficultiesfor rational discussion as does the bear-ing of genetic research on human wel-fare. It is monotonously coupled withsuch inflammatory themes as racism,the decline of the species, overpopula-tion, hidden genocide, religious debateson abortion and contraception, theplight of the individual in mass society,and ‘how many generations of idiots isenough?’ “~~

Graham Chedd, in a recent issue ofScience 81, examines many of theethical implications of genetic screen-ing. “There is also the fear that abortionfor genetic disease could graduallyevolve from being the ‘responsible’ tobeing the ‘expected’ thing to do,” hewrites. “Proponents of genetic abortionargue that knowing a fetus is defectiveincreases the prospective parents’ free-dom of choice . . . . But seeing the bene-fits to society of mandato~ abortionisn’t difficult. Perhaps the deepest ap-prehensions about the use of geneticabortion stem from the ever-increasingrange of prenatal diagnosis. If we see itas acceptable, even responsible, toabort now for Down’s syndrome, whatwill be the attitude in the future when,say, muscular dystrophy can be diag-nosed prenatally?”%

A number of legal questions have alsobeen raised about the physician’s obliga-tion to provide genetic counseling andinform patients about prenatal diagnos-tic tests currently available. Several‘“wrongful life” lawsuits have beenbrought against physicians by parentsand children because of the doctors’failure “to detect or disclose thepossibility that a defective child will bebO~. ”55

Despite these questions, the value ofgenetic screening has been recognizedby many governments, as well as re-

searchers and physicians. In 1976, theUS Congress passed the National Genet-ic Diseases Act which provides for a na-tional program of information and edu-cation in connection with geneticdiseases. 56 A National Clearinghousefor Human Genetic Disease has beenestablished under this act, and fundinghas been provided to the states forgenetic services.J In Canada, which hasa universal health insurance program,the government afso sponsors resourcesfor the screening, diagnosis, counseling,and treatment of heredhary disease. 11The Clinical Genetics Society in the UKrecently prepared a report outlining thetraining requirements and functions ofthe medical geneticist .57

Although the preventive implicationsof this field are recognized, there is stillsome resistance to the incorporation ofhuman genetics into medical practice.Barton Chdds, Johns Hopkins Universi-ty, reports that few physicians surveyedin 1975 considered genetic disease aserious practical problem.~ As I men-tioned in the preventive medicine essay,physicians are more concerned with“curing” patients of specific diseasesthan with preventing future illness.Childs also cites the physician’s concernwith indkidual patients, rather thanfamilies, and the episodic nature ofmedical treatment, as factors preclud-ing the application of med]cal geneticsto standard medical practice. In a faterarticle, he points out that medical ge-netics is usuafly a minor part of themedical school curriculum, and is oftennot clinically-oriented. 59

With more research on human genet-ics will come greater recognition of thepreventive, or “predictive,” value ofmedical genetics. Already, researchersare finding ways to track the inheritanceof genetic disease through differences inthe DNA at specific regions of the chro-mosome, calfed DNA polymorphisms.David Botstein, MIT, and RaymondWhite, University of Utah, are tracingthe inheritance of these markers

231

through several generations, and inves-tigating the relationships between thesemarkers and specific genetic diseases. ~Currently, other “markers,” or traitscarried by a gene on the same chromo-some that carries the gene for a geneticdisease, are used to trace inherited dis-ease in families. These include bloodgroup, color bliidness, serum proteinpolymorphisms, the ability to tastephenylthiocarbamide, and HLA an-tigens.

Associations have been made be-tween HLA antigens and such diseasesas rheumatism, ankylosing spondylitis,arthritis, psoriasis, asthma, and Hodg-kin’s disease.bl.bz There may also be anassociation between these antigens andjuvenile onset diabetes and myastheniagravis.61 Unfortunately, blood tests forthese antigens are fairly expensive anddifficult. Scientists are also mapping thelocations of genes on chromosomes,and investigating transplantation andreplacement of defective genes.b$~ Ac-cording to McKusick, “We now knowthe speciiic chromosome canying eachof over 450 human genes and the specif-ic localization of that chromosome isknown for many of these. For somesegments of the DNA the anatomy isknown now down to the individualnucleic acids. ”lQ

Medicaf genetics is a field that fre-quently interfaces with other areas ofbiomedical research. Several of thehighly active specialties in ISI/BIO-MED ‘“ that deal directly with medicalgenetics touch upon many of the dis-eases and research areas I’ve mentionedhere (see Table 1). For example, wehave one research front that deals ex-clusively with genetic aspects ofalcoholism, and several that deal withgenetic aspects of cancer and otherdiseases.

Among the many co-citation clustersproduced from our data base, there areseveral which focus on genetic diseasescaused by enzymatic deficiencies. Thework of McKusick and colleagues is

particularly relevant to thk essay and tothese chssters.bS-bT McKusick, who willappear on our forthcoming list of 1,003most-cited authors, is probably bestknown for his catalog of geneticdiseases~ and was one of the earliestclinicians to promote an understandingof the role of genetics in human disease.The entries for this catalog, which wasfirst published in 1966, are kept in acomputer fide that is continuously up-dated. A recent count, in June, revealedthat about 3,254 genetic loci have beenidentified, half of which “were quiteclearly identified as real and distinct, ”and haff of which were tentatively“identified and included for heuristicpurposes and none other. “19

The growth of this field is alsoevidenced by the presence of medicalgenetics papers in a wide range of jour-nals, inchsdmg Lancet, Journal of theAmen”can Medical Association, Ameri-can Journal of Psychiatry, and NewEngland Journal of Medicine. A num-ber of the popular science magazinesalso publish articles on medicalgenetics.

The major sources of journalliterature on the subject are the Ameri-can Jouma[ of Human Genetics, Amen”-can Journal of Medical Genetics, An-nals of Human Genetics, Human Ge-netics, Journal of Medical Genetics,and Clinical Genetics. All are coveredby the Science Citation Indexa,ASCAm, and Current Contents@ /LifeSciences. The Amen”can Journal ofMedical Genetics, Clinical Genetics,and Journal of Medical Genetics arealso covered in Current Contents/Clini-cal Practice. These, and several otherjoumafs that publish papers related tomedical genetics, are presented in Table2 along with the number of articlespublished in 1980; the number of cita-tions received in 1980 by articlespublished in these journals; their impactfactor, a measure of the frequency withwhich the average 1978/ 1979 article hasbeen cited in 1980; and their immediacy

232

TabEe 1: Some of the genetic d~ease research front specialties identfited by co-citation analysisin ISI/BIOMED ~U

GENETICGENETIC

The AH-LOCUS ●nd GENETIC control ofCARCINOGEN METABOLISM 19800258

COLLAGEN }ynthesn ●nd GENETICPOLYMORPHISM I 9800479

ENvIRONMENTAL CttEMlCAL5 ca@mg CANCERand GENETIC BIRTH OEFECTS 1980 1204

EVOLUTION ●nd GENETIC VARIABILITYlQRfl 1R72. . -----

GENETIC and ENVIRONMENTAL etfects on DRUGMETABOLISM 1980 1868

GENETIC q)ecfs of ‘ALCOHOLISM 19801506GENETIC control ot CELL-MEDIATED IMMUNE

RESPONSIVENESS 19802087GENETIC c~kd of COMPLiMENi ‘+FYOTEIN

structure bv the HISTIXOMPATIBILITYCmpw .“ 19800100

GENETlc control Oi tYTtii+’ROhiEp-45019800258

GENETIC control of HYDROXYIASE xtw! PIQ (ll&<7--------GENETIC COftfd of T-CELL SPECIFICITY

19800342GENETIC confrd of TUMORIGENICITY m HYBRID

CELLS. 1980 1787GENETIC ●tfecfs ot DYES M’ ONA 1980 1936GENETIC w ●mzafmn of NEMATOOE

CAENOR%ABDITIS. ELEGANS 19800684GENETIC studw of AGRO~ACTERIUM

19800616GENETIC vanatma 1980 1033GENETIC DETERMINANTS of remitkc to

ANTIBIOTICS b NEISSERIA.GONORRHOEAEiandofher BACERIA . . . . . . . 1980-0240

GENETIC MAPPING of HEAT-SHOCK INDUCIBLE.GENES m DROSOPffltAMEMNDGA TER

?1 80 1653GENETIC POLYMORPHISM m FINITE

..,. - ,. .-. -.,- 1980 1616)Rbitishi “Of iitiHROcYTE

s 198013175CIXNITION “and’ crkol SEQUENCES

b.. . 19802273IN of ON”CDGENIC

VIRUSES 19800325GENETIC REsTRicTto”fi Of kiACROpNAGE T.CELL

mtemctmrm 1980 1261GENETIC, ENVIROtiMEN”TAL, and t.iIkTARY

confnbubons to CHILDHOOO ●ndADOLESCENT GROWTH dynam,cs

1980. ?79?

—Ullvn>GENETIC POLVMC

FU7VUF(. -------GENETIC RE

m the NUCLEIC-ACIDSGENETIC RECOMBINATION

. . . .MODELS of GENETIC control of ENZYME actw

?198021 0

GENETIC.LINKAGEGENETIC-LINKAGE ●lUtyUL for RECESSIVE

dmeasu 19801243

GENETICALLYPHYSIOLOGY of GENETICALLY OBESE m,ce

19800681

GENETICSBACTERIOPHAGE.LAMBOA GENETICS

19800040GENETICS of mouse LELJKEMIA.VIRUS

1980.0917GENETICS of BACTERIAL RNA-POLYMERA ES

8198 .1841MOLECULAR GENETICS of human HEM

,%%’?,MOLECULAR GENETICS of FETAL HEM

1$%%? 1MOLECULAR GENETICS of MITOCHONDRIAL

DNA 1980.063 ?MOLECULAR GENETICS Ot TiALASiEMIA

198 0271

‘wMT’ON ‘ENET’CS 0’ “O’w!l%noTERATIXARCINOMA TRANSPLANTATION STEM

CELL GENETICS ●nd IMMUNO.REJECTIONLOCI 19800232

HYPERCHOLESTEROLEMIANuTRITION ●-d HYPERCHOLESTEROLEMIA

19800B59RISK. ASSESSMENT of FAMILIAL

HYPERCHOLESTERDLEMIA andHYPERLIPIDEMIA 19802258

lfYPERLiPfOEMIADIET ●nd HYPERLIPIDEMIA 1980 )640RISK ASSESSMENT of FAMILIAL

MYPERCHOLESTEROLEMIA andHYPERLIPYDEMIA 19802258

LESCH.NYHAN-S YNl?ffOMEPURINE synthe$ts, HPRT def!cwncy, ●nd LESCH

NYHAN SYNDROME !980 1937

M(JSLXJL4R.D YSTROPHYCYTOPATHOLOGY ●nd PATHOPHYSIOLOGY of

MUSCULARDYSTROPHY 19802030ERYYHRDCWE PUStAA+4EW3RANi

ABNORMALITIES m DUCHENNE MUSCLJLA RDYSTROPNY 198017)4

S/CflLE-CELLGELATION of SICKLE CELL HEMOGLOBIN

19801690

T)iAIASSEMIAIRON CHELATION THERAPY for THAIASSEMIA

and oftw c!+rwalsfate8 produang IRONOVERLOAD 1980.0369

TtiAUSSEMIASMOLECULAR GENETICS of THALASSEMIA

8198 .0271

lJLTRASOFVLXRAPWCULTRASONDGRAPHIC meawrement of

GESTATIONAL AGE 19800823

index, a measure of how quickly the I tioned before, a National Clearinghouse. .average article published in 1980 wascited.

Several computerized data bases arecurrently being developed, includingtwo at Columbia Universit@f and theUniversity of California at San Fran-cisco,~ that are expected to serveresearch, service, and administrativeneeds in medical genetics. As I men-

for Human Genetic Dkease has b~en es-tablished under the National GeneticDiseases Act. This clearinghouse, whichcan be contacted at P.O. Box 28612,Washington, DC 20005, provides infor-mation on genetic screening and treat-ment programs. An annual course inmedical genetics and experimentalmammalian genetics is offered jointly

233

Table 2: Selec!ed list of medical genetics journals ccwered by Currenf C’on@nf.r’ and theScience Cifar,on Indexz, wit b the total number of articles they published in 1980, the totalnumber of citations they received in 19S0, their impact factor, and [heir immediacy index.Source: 1980 SCP Joumoi Cmzzmn Repotis’>’

1980 1980Artkles Total Impact Immcdkcy

Pubfkhed Chatiom Factor Index

Advances in Human Genetics 5 122 ,429 .MX1American Journal of Human Genetics 89 2431 3.643American Journal of Medical Genetics

.382108 206 .944 .139

Annals of Human Genetics 33 1334 1.602 .697Annales de Genetique 63 679 1.375 .095Behavior Genetics 43 443 I .594 .256Canadian Journal of Genetic Cytology 53 884 1,024 .208Clinical Genetics 136 1340 1.566 .169Clinical Pediatrics 131 802 .478 .031Genetical Research 51 1133 I .070 ,294Genetika 229 955 .372 .240Hereditas 85 1810 1.701 .329Heredity 71 I573 1.309 .394Human Genetics 223 2254 1.7b3 .318Human Heredity 73 594 ,894 .137Japanese Journal of Genetics 48 452 .828 .292Japanese Journal of Human Genetics 2-? 145 .774 .222Journal de Genetique Humaine 44 156 .400 .091Journal of Heredity 110 1438 ,694 ,{27

Journal of Medical Genetics 109 1304 1.221 ,183Tk.sue Antigens I20 I4s3 1.657 .233

Iby Johns Hopkins University and Jack- I North Carolina 27709, or the Geneticsson Laboratory. For information on thiscourse, which has been offered since1960, contact Victor McKusick, JohnsHopkins Hospital, Baltimore, Maryland21205, or Thomas H. Roderick, JacksonLaboratory, Bar Harbor, Maine 04609.

A number of organizations exist forprofessional geneticists and individualsinterested in, or affected by, geneticdkease. The American Society of Hu-man Genetics, c/o Judith Brown, Secre-tary, Box 33 MCV Station, Richmond,Virginia 23298, is a professional societyof physicians, researchers, teachers,genetic counselors, and others in thefield. The American Genetic Associa-tion, 818 18th Street, NW, Room 250,Washington, DC 2C@6, includes biolo-gists, zoologists, geneticists, botanists,and others in academic or governmentresearch. Individuals interested in anyfield of genetics can contact theGenetics Society of America, throughits president, Burke Judd, NIEHS, P.O.Box 12233, Research Triangle Park,

Society of Canada, through its presi-dent, R.C. Von Borstel, University ofAlberta, Department of Genetics, Ed-monton, Alberta T6G 2E 1, Canada.The International Genetics Federation,P.O. Box 1600, Canberra 2601, Austra-lia, is comprised of societies concernedwith both human genetics and plantbreeding, and the Behavior GeneticsAssociation, which can be contactedthrough the Institute for BehavioralGenetics, University of Colorado,Boulder, Colorado 80309, is a profes-sional organization for individualsengaged in teaching or research in somearea of behavior genetics. The NationalGenetics Foundation, 555 West 57thStreet, New York, New York lCOl 9,conducts educational programs for thepublic and physicians and operates anetwork of genetic counseling and treat-ment centers. The National Society ofGenetic Counselors can be contactedthrough Beverly Rollnick, Center forCranialfacial Abnormalities, University

234

of Illinois, Abraham Lincoln Center,470-DMP, P.O. Box 6998, Chicago, 11-Iinois 6068Ll. The international Societyfor Twin Studies can be contacted at theMendel Institute, Piazza Galeno 5,00161 Rome, Italy, and the Associationfor Research into Restricted Growthcan be contacted through Valerie Sims,Secretary, 5 Peak Walk, Witham,Essex, England.

There are also a number of voluntaryorganizations concerned with heredi-tary diseases. Included among these arethe Hereditary Disease Foundation,9701 Wifshire Boulevard, Beverly Hills,California 902 12; the March of DimesBirth Defects Foundation, 1275 Mamar-oneck Avenue, White Plains, New York10605; National Tay-Sachs and AlliedDiseases Association, 122 East 42ndStreet, New York, New York 1(X)17;Cooley’s Anemia Foundation, 420 Lex-ington Avenue, Suite 1644, New York,New York 10019; Cystic Fibrosis Foun-dation, 3379 Peachtree Road, NE,Atlanta, Georgia 30326; National Asso-ciation for Down’s Syndrome, FullertonAvenue, Addison, Iflkois 60101; Na-tional Foundation for Jewish GeneticDiseases, Inc., 609 Fifth Avenue, Suite1200, New York, New York lCN)l7; Na-tional Association for Sickle CellDiseases, Inc., 3460 Wilshire Boule-vard, Suite 302, Los Angeles, California90010; National Hemophilia Founda-tion, 25 West 39th Street, New York,New York 10018; National Huntington’sDisease Association, 128A East 74thStreet, New York, New York 10020;Spina Bifida Association of America,343 Dearborn Avenue, Room 319, Chi-cago, Illinois 60604; Parents HelpingParents, 47 Maro Drive, San Jose,California 95127; and Little People ofAmerica, P.O. Box 633, San Bruno,

California 94066. Associations outsidethe US include Little People’s Associa-tion of Australia, c/o Robert Wood,10/ 16 Roslyn Gardens, Elizabeth Bay,NSW 2011, Australia; Les Petits Tailles,c/o Claude Stoll, Institut de Puericul-ture, Hospices Civils, 6730 Strasbourg,France; World Federation of Hemophil-ia, 1170 Peel Street, Suite 1126, Mon-treal, Quebec H3H 2J 1, Canada; andAssociation for Research into Re-stricted Growth, c/o Mary Lindley, 2Mount Court, 81 Central Hill, LondonSE19 lBS, England.

Medical genetics is making inroadsinto standard medical practice. Bloodtests given adults are regularly screenedfor the presence of genetically influ-enced high cholesterol and triglyceridelevels. Obstetricians are advising olderpregnant women to take diagnostictests. As McKusick pointed out in a re-cent letter, “ . .man is rapidly becomingthe best studied of the mammals fromthe genetic point of view..., The big ad-vantage that man has as an object ofgenetic study is, of course, the anthro-pocentric interest in our own speciesand the fact that we have such a largesegment of the world’s population work-ing for us, in effect, cofIecting informa-tion on human variation from an ana-tomic, physiologic, pathologic andbiochemical point of view.”lg However,before all this information can be usedto fully benefit human health, a greatdeal of research must stilf be done onthe detection, hereditary patterns, andtreatment of genetic diseases, and easilyadministered, inexpensive tests must bedeveloped to fmd them.

● ****My thanks to Joan Lipinsky Cochmn

and Patn”cia Heiler for their help in theprepamtion of this essay. OW ,s$

REFERENCES

1. Gdf&J E. 1s preventive medicine taking off at last? Current Contents (52):5-IO, 29 December 19S().2. Smdek D. Personal communication. 8 January 1981.3, McBee J R. Telephone communication. 12 May 1981.

235

4. Fraaer F C. introduction: the development of genetic counseling.Birth Defects 15:5-15, 1979.

5. Gmrfsw F H. An introduction to the history of medicine.PhiJadclphia, PA: Saunders, 1921.942 p.

6. Dunn L C. Cross currents in the hktory of human genetics.Amer. J. Hum. Genet. 14:1-13, 1%2.

7. Reed S C. A short history of human genetics in the USA.Amer. 1. Med. Genet. 3:282-95, 19’79.

8. GJwJkdd E. Would Mendel’s work have been ignored if the Science Citation Indexa wasavailable lW yearn ago? Currenf Confeno (2):5-6, 14 Januaey 1970, ”

9, ZJr&JeC. Some oddities in the delayed discovery of Mendefism. J. Hered. 55:65-72, 1964.10. CaJSlan A. Genetic counaeliig, medical genetics and theoretical genetics: an historical overview.

Birth Defects 15:21-31, 1979.11. Scrfver C R, J.afserge C, Cfow C L & Fraser F C. Genetics and medicine: an evolving

12,

13,

14.15.16.

17.

18.

19.20,

21.22.

23.

24.

25.

26,

27.28.

29.

30.31.

32.33.3435.3637.

39

relationship. Science 203:946-52, 1978.Garrod A E. Inborn errors of metabolism.

London: Frowde and Hodder & Stoughton, 1927.202 p.Berkow R, ed. General principles of medical genetics. The Merck manual of diagncmi$

and thempy. Rahway, NJ: Merck Sharp & Dohme Research Laboratories, 1977.p. Iw-f 13.

Tjb J H & LevuI A. The chromomme number of man. Hereditas 42:1-6, 1956.Ford C E & Hainerion J L. The chromosomes of man. Nature 178:1020-3, 1956.lacobs P A & Strong J A. A case of human intersexuality having a poaxible XXY xex-

de!ermining mechanism. Nafura 183:302-3, 1959.Ford C E, Jones K W, MfDer O J, Mfttwncb U, Penrose L S, RfdJer M & .$Jmpfm A.

The chromosomes in a patient showing both mongolism and the Kfinef elter syndrome.Lancer 1:709-10, 1959. ,

Lejerme J, Gautfer M & TurpfII R. Etude des chromosomes somatiques de neuf enfan[sMongolians. C.R. A cad. Sri. Ser. D 248:1721-2, 1959.

McKwkk V A. Personal communication. 15 July 1981.Murray J A H, Brmffey H, CraJSie W A & OnJom CT, eds. The Oxford English

dictionary. New York: Oxford University Press, 1%1. p. 6.$i.Fuchs F & RJis P. Antenatal sex determination, Nature 177330, 1956,Steele M W & JJreg W R. Chromosome analysis of human amniotic-fluid cefls,

Lance! 1:383-5, 1%6.Thfede H A. Creammn W T & MetcafJe S. Antenatal analysis of the human chromosomes.

Amer. J. Obslet. Gynecol. 94:589-90, 1%6.EpsteJn C J & Golfms M S. Prenatal diagnosis of genetic dixeases.

Amer. Sci. 65:703-11, 1977.The Ndcmd Imat+tuteof CJdJd Heaf@ ●nd Human Development Nasfonaf RegJsery for

Amnfocen:eah Study Group. Midtrimester amniocentesis for prenatal diagnosis.J. Amer. Med. Assn. 236:1471-6, 1976.

Dodd I & Brown T G. Localisation using physical devices, radioisotopes and radiographicmethods, I—Demonstration of tissue interfaces within the bcdy by ultrasonic echo sounding.Bnt. J. Radioi, 34:539-46, 1%1.

Wwtfri B. Letter to editor. (Hysteroscopy in early pregnancy). Lancer 2:872, 1954.------------- Technique and estimation of oxygenation of the human fetus in utero by means

of hystero-photography, A eta Paediar. C/ppsala 46:1 I7-24, 1957,StnckJmsd L & Marks S A, A new method of fetal weight determination.

Amer. J. Roentgenol. 86:425-32, 1%1.FWUZWJCYA. Know your genes. Boston: Houghton MIfffii, 1977.335 p.JJmek D J H & SutcMfie R G. ,+fpha-fetopmtein in the antenatal diagnosis of anencephaly

and spina bf}da. Lancef 2:197-9, 1972.Sobel D. Simple test could affect most expectant mothers. NY Ttme$ 13 Janua~ 1981, p. CI-C2.

Brock D J H. Citation Classic. Current Conlenr$/Clinical Pmctice 9( 16):18, 20 Aprif 1981,f%snnett H. Telephone communication. 12 June 1981.Levfne C. Genetic counsefiig: the cfient’s viewpoint. Bitih LJe,fecr$ 15:12.3-35, 1979.Opftz J M, ed. (whole issue). Amer. J Med. Gene~ 7(4), 1980.547 p.MJb L H, Mason S J, Dvorak J A, McGhmkss M H & Rothmmr J K. Erythrocyte

receptorx for (Pla$modiurn knu wkzri) malaria: Duff y blood group determinants.Science 189:561-3, 1975.

Smfver C R. The William Aflan Memorial Award addres cm phosphate transport and geneticxcreening. Understanding backward—living forward in human genetics.Amer. J. Hum. Genet. 31:24363, 1979.

Lynch H T, FatQ P & Marrero K. /ntema(iona/ directory of generic serk,ice$.White Plains, NY: March of Dimes Birth Defects Foundation, 1980.54 p.

236

40

41,42.43,

44.

45,

46.

47.

48.

49.w,51.

52.

53.

5-4.55.

56.

57.58.

59,

6Q.

Pustik D T, Paquin L & Gtmfhaxt T. Genetics of neoplasia-impact of ecogenetics ononcogeneak. Amer. J. Pathol. 91:609-81, 1978.

AfJen G. Scope and methodology of twin studies. Act. Gene-t. Med. Gemellol, 2S:79-85, 1976.Nancc W E. The use of twins in cfinical research. Birth Defects 13:19-44, 1977.Tsuang M T. Genetic counseling for psychiatric patients and their families.

Amer. J. Psychiat. 135:1465-75, 1978,Garffeld E. what do we know about depression? Part 1: etiology.

Current Conteno [19):5-12, 11 May 1981,--------------- Senifity: a major heaJth problem in need of a solution.

Curmnf Conteno (24):5-9, 15 June 1981.Wfnofmr G. Genetic findings and methodological considerations in manic depressive disease.

Brir. J. Psychiat. 117:267-74, 1970.Omenn G S & MotuJaky A G. “Ecu-genetics”: genetic variation in susceptibihty to envirnnmentaf

agents. (Cohen B H, L~lenfeld A M & Huang P C, da. ) Genetic issue~ in public health andmedicine. Springfield, JL: Thomas, 1978. p. 83-111.

Garffefd E. The worldwide problem of lactose intolerance.Current Contents (49):5-8, 8 December 1980.

Prnppfng P. Pharmacngenetics. Rev. Physio[. Biochem. Pharmacol. 83:12373, 1978.Muffer H L Artificial transmutation of the gene. Science M:84-7, 1927.Tdmbfe B K & Smfth M E. The incidence of genetic dueaae and the impact on man of an

altered mutation rate. Can. J. Genet. Cyto{, 19:375-85, 1977.Oftedaf P & Searle A G. An ovemff genetic rink aaaeasment for radiological protection

purposes, J. Med. Genet. 17:15-20, 1980,Lederberg L Genetic engineering and the amelioration of genetic defect.

Bioscience 20:1307-10, 1970.Chedd G. Wrongful life. Science 81 2(1):40-1, January/February 1981.Peters I D & Peters B M. Wrungful fife: recognizing the defective chdds right to a cause of

action. Duquesne Law Rev. 18:857-76, 1980.National Sickle Ce{l Anemia, Cooley k Anemia, Toy-Sachs, and Genefic Diseases Act,

Pub. L. No. 94-27842 U.S.C, $3$3 b (1976).Iobnston A W. The tratimg of medical geneticists in Britain. Amer. J. Med. Genet. 3:7-9, 1979.CbEda B. Persistent echoes of the nature-nurture argument.

Amer. J. Hum. Genet. 29:1-13, 1977.CMMs B, Huether C A & Murphy E A. Human genetics teaching in US medical

schwds. Amer. J. Hum. Genet. 33(1):1-10, 1981.Botatefn D, Whfte R L, Skofnkk M & Davis R W. Construction of a genetic finkage map

in man using restriction fragment length polymorphisms.Amer. J. Hum. Genet. 32:314-31, 1980.

61. Cohen E. JfL.A-B-27 and ankyfosing spondylitis.Glendale, CA: Hyland Therapeutics Di*lon, Travenol Laboratories, Inc., 1980, 8 p.

62. Rogentfne G N. HLA and disease. Natura 262:3S)-1, 1976.63. McKuakk V A. The anatomy of the human genome, Amer. J. Med. 69:267-76, 1980,64, Norfng S. Cliical genetics comes of age. Columbia 6(4):21-3; 41, Spring 1981.65. McKuskk V A, Kaplan D, Wfse D, Hmdey W B, Sudderth S B, Sevkk M E &

Maumnms A E. Tlte gemetic mucopolyaaccharidoaes. Medicina 44:445-&3, 1%5.66. McKuakk V A. Howefl R R, Huaaela I E, Netdeld E F & Stevenson R E. AMiam,

non-allelism, and genetic compounds among the mucopolyaaccharidoscs.Lancet 1:993-6, 1972.

67. McKuakk V A. Heritable disorders of connective tissue. St. kmia, MO: Mosby, 1972.878 p.68. --------------------- Mendelian inheritance in man.

Baltimore, MD: Jofms Hopkins University Press, 1978.975 p,69. Lm@man W D, MltcheJf J A, Mosher D C & Epstefn C J. Genfiies: a computerized

medical genetics information network. 1. An overview. Amer. J, Med. Gene/. 7:243-50, 1980.

“Reprinted in: Garffekf E. Emnys of an information $cientisr. Philadelphia 1S1 Press, 1980.3 vola