A Contribution to the Differential Diagnosis of the"Group of Schizophrenias": Structural Abnormality of

Chromosome 4

R. M. Palmour1, S. Miller2, A. Fielding', M. Vekemans2 , F.R. Ervin' 2

'Department of Psychiatry, McGill University, Montreal, Quebec.2Centre for Human Genetics, McGill University, Montreal, Quebec.3Division of Medical Genetics, McGill University, Montreal, Quebec.

Submitted: February 10, 1993Accepted: February 17, 1994

A structural abnormality of chromosome 4 [inv 4 (pl5.2; q21.3)] is reported in a male presentingwith DSM-III-R schizophrenia, undifferentiated type (295.94) and in his mother, who displayedsymptoms associated with schizotypal personality disorder (DSM-III-R 301.22). The proband hada performance IQ of 91, poor motor coordination, stature in the lowest quartile and an impairedsense of time. There were no diagnostic physical or neurological abnormalities. Mild ventricularenlargement and prominent sulci were found on computed tomography. Both he and hischromosomally normal father had strabismus which required surgical correction. This case joinsthe long list ofchromosomal abnormalities previously reported to confer an increased risk ofmentalillness and emphasizes the importance of a sophisticated differential diagnosis in evaluating patientswho present with symptoms of schizophrenia. The implications for recent initiatives which attemptto localize genes conferring susceptibility to schizophrenia and other major mental illnesses are

discussed.

Key Words: schizophrenia, psychotic disorder, inversion, chromosome, nosology

INTRODUCTION

Bleuler, in his classic work Dementia Praecox oderGruppe der Schizophrenien (1911), called attention to theintrinsic heterogeneity of the disorder which, throughout thiscentury, has formed the core problem of psychiatry. Hisinsights were grounded in many years spent observing un-medicated persons consigned to a research mental hospital.This concern for heterogeneity was limited to an array ofcases with primary disturbances in thought and affect andwho displayed documented variability of ages of onset, ratesand patterns of disease progression and secondary phenom-

Address reprint requests to: Roberta M. Palmour, Ph.D., Depart-ment of Psychiatry, McGill University, 1033 Pine Avenue West,Montreal, Quebec, Canada H3A lA1.

ena such as hallucinations, delusions, catatonia, languagedisturbances, etc. Patients with the rather similar psychosesinduced by bromism, mercury poisoning, pellagra and terti-ary syphilis were already excluded at this early date. Evenlater, Gjessing (1961) recognized a separate recurring cata-tonia with unique and characteristic metabolic dysfunction.In the intervening years, many other organic causes of'schizophrenia' have been noted. Some of the more promi-nent are structural abnormalities of the brain (Davison andBagley 1969), chronic temporal lobe epilepsy (Slater et al1963), adult onset metachromatic leukodystrophy, acute in-termittent porphyria and other inborn errors of metabolism(reviewed by Propping, 1983), as well as chromosomal ane-uploidies and rearrangements (Propping 1983; Crow 1988;DeLisi and Lovett 1990; Bassett 1992).

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Inversion ofchromosome 4 in schizophrenia

Fig. 1. Pedigree of Family 8906.

Schizophrenia, as we know it today, is not a disease, butrather a syndrome defined by the presence of specific symp-toms and the absence of plausible etiologic pathophysiology.According to convention (DSM-III-R or ICD), a diagnosis ofschizophrenia is excluded if there is an identified organicdisorder sufficient to cause the brain disturbance. The differ-ential diagnosis of schizophrenia must thus include the array

of structural, metabolic, endocrinological, toxic and chromo-somal abnormalities which sometimes present as "schizo-phrenia-like psychosis." (Throughout this manuscript theterm "schizophrenia-like psychosis" will be used to identifythose disorders which display behavioral signs and symp-

toms of schizophrenia but which are generally thought to bethe consequence of organic impairment. "Schizophrenia" isused as defined in DSM-III-R and DSM-IV.)

Indeed, one could argue that a proper task of researchpsychiatry is to identify, over time, all ofthe possible organiccauses of the syndrome we presently term schizophrenia. Anunappreciated corollary is that these cases are then removedfrom the syndrome of schizophrenia so that we still do notknow an organic basis for this severe disorder. Be that as itmay, this information is obviously relevant to the appropriatemedical care of these patients, and an appreciation of thediagnostic process should also guide molecular attempts toidentify the specific genetic contributions to schizophrenia.The following contemporary case provides several illustra-tive clinical points and emphasizes some current issues aboutthe relationship between rare causes of schizophrenia and theresiduum of this common and debilitating disorder.

Case report

The proband (see Figure 1), a white male with an IQ of91, first came to psychiatric attention at the age of 19 becauseof repeated episodes of belligerent and aggressive behavior.He was born weighing 3.35 kg after a normal term pregnancyin a para three mother of 41 years. There was no suggestionof chromosomal abnormality at birth or in childhood anddevelopmental milestones were achieved at appropriate ages(he sat at seven months, pulled up at nine months, walked at14 months and produced his first words at 15 months.) By theage of three, however, he was in the lowest quartile for heightand weight and began to experience social and learningproblems in primary school. Throughout primary school theproband was referred on several occasions for testing, but thechart states that his mother was reluctant to follow thisrecommendation. In secondary school his adaptation report-edly improved and the proband completed grade 11, albeit inSpecial Education. He was then placed in a semi-shelteredworkshop for vocational training.

The initial psychiatric referral was a consequence of im-pulsive violent outbursts during which he was physicallycombative. Somewhat later, suicide was attempted. Impulsedyscontrol and agitated depression were present during theearly stages and thought disorder and paranoid anxiety be-came apparent within the first year of psychiatric interven-tion. At the time of our evaluation, the proband (25 years ofage) had been under psychiatric care for six years and hadexperienced repeated placement in sheltered workshops, fos-ter homes and group living; each of these situations wasterminated after an initial satisfactory period and a period of

&At Ag /~~~~~+++*+n*v 4 (p15.2; q21.3); Schizophrenia-like psychosis I Agitated aggressive depression* Inv 4 (p15.2;q21.3); Schizotypal symptoms U Depression?El Normal karyotype ++ Karyotyped

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slow decline. There was marginal improvement in socialadaptation but not in the thought disorder upon treatmentwith standard antipsychotic medications. However, if hisneuroleptic medications were reduced or discontinued, herapidly regressed and aggressive episodes reappeared, basedapparently on the paranoid process. The proband has requiredhospitalization 14 times in the last nine years, typically as aconsequence of uncontrolled aggressive episodes or floriddelusional states. He has been well oriented throughout as toperson, time and place and has presented no evidence oforganic psychosis.

Psychiatric presentation

The proband met formal DSM-III-R criteria for a diagno-sis of schizophrenia with thought disorder and delusions asthe major symptoms; this diagnosis had been independentlyassigned over the last nine years by at least four clinicians(DSM-III-R 295.94). A precise onset of symptoms could notbe determined, but the proband had never achieved goodsocial relations and had never worked effectively in schoolor thereafter. Nonetheless, there had been a deterioration offunctioning and this was especially apparent when medica-tion was discontinued. Persecutory delusions, loosening ofassociations, concrete and illogical thinking and markedpoverty of speech were characteristic of active phases. Dur-ing neuropsychological testing, he voluntarily reported ideasof reference and seeing an imaginary little man standing onthe desk. Inappropriate affect and impulse dyscontrol to thepoint of arrest and prosecution were often prominent as well.The residual phase had been marked by increasing socialisolation, increasing deterioration in work roles and flat orinappropriate affect.

The proband's delusions were persecutory, often havingto do with women. His intrusive thoughts also were mostoften focussed upon women in general, and women in posi-tions of authority in particular, and they combine with hisfrustration at having no social and/or sexual relationshipswith women and his fear of being harmed by women. Hisovertly aggressive outbursts were typically, but not always,directed against women and only occurred after consumptionof moderate quantities of alcohol. In addition, he displayedpoorjudgment to the extent of putting himself at physical riskand had little or no concern for the consequences of hisactions. Following one episode of drinking, he casuallysnapped off the radio antennae on several parked cars, lead-ing to physical pursuit and attack by local males. Moregenerally, he repeatedly failed to respect the boundaries setby caretakers or residential group supervisors.

Physical findings

Physically, the proband was poorly coordinated, of shortstature (1.53 m) by comparison to his father (1.67 m), andaccording to his chart gave the appearance of being slightly

dysmorphic. However, neither specific physical abnormali-ties nor diagnostic neurological findings were confirmedupon objective examination. A moderately severe strabismuswas surgically corrected several years prior to our examina-tion. Head circumference (45 cm) was in the lower sextileand a high forehead was noted. Secondary sex characteristicswere described as normal by the examining geneticist. Hehad poor posture, walked with a shuffling gait and displayedmild extrapyramidal signs. There was no malformation ofmajor organs. A CT scan with contrast revealed mild ven-tricular dilatation with prominence of cisterns and sulci.There was no displacement of midline structures. The radi-ologist concluded that mild cerebral atrophy was present andthis was consistent with the small head circumference. AnEEG showed an increase in low voltage ,B fast activity anddiffuse 0, but was judged to be clinically normal.

Intelligence testing was carried out in grade seven (globalscore 92), and later at the time of psychiatric referral. VerbalIQ in 1986 on the Barbeau-Pinard was 98, nonverbal was 83and global was 91. Additional neuropsychological testingwas attempted but could not be completed during the initialsession because of extreme slowness, despite a cooperativedemeanor. Upon later testing, it was found that visual mem-ory, visual motor skills and arithmetic comprehension wereparticularly impaired but speech comprehension was good.Pronounced failure to perceive the passage oftime accuratelywas revealed during both neuropsychological testing ses-sions and in the workplace. This characteristic had recur-rently led to the proband's dismissal from employmentopportunities in sheltered workshops, etc.

The failure to appreciate time had appeared in somecircumstances to be the result of daydreams or fugue states.During neuropsychological testing, for example, if left tocomplete a pencil-and-paper task, he typically worked wellfor two or three minutes, then began to stare into space or toperseverate over the details of his task. The proband alsosometimes exhibited motor automatisms; when questioned,he denied that these had ritualistic content or obsessionalcharacter. These historical symptoms suggested possible epi-sodes of subcortical ictal activity (perhaps complex partialseizures), but there was no confirmation of this on routineEEG at age 22.

Endocrine values were normal, as was biochemistry(SMAC 30). A VDRL was negative. Chromosomes wereordered because there was small stature, low head circumfer-ence and minor physical findings. Routine Giemsa and qui-nacrine banded smears showed a 46, XY, 4p+ (?) karyotypein the proband, an apparently indistinguishable karyotype forthe mother and a 46, XY karyotype for the father.

Genetic evaluation

The kindred came to genetic attention when the proband'syounger sister (Figure 1) requested counselling about her riskof having a child with an illness similar to that of her brother.

272 VoL 19,, No. 4,1994

Inversion ofchromosome 4 in schizophrenia

A B

6 7 6 9 10 tl 12 X

C

)~~

13 .4 15

I9 I

F

2a.

Ks i5 !-16 17 16

E

2 _

2, 22 Y

G

2b.

Fig. 2. Prometaphase banded karyotype of the proband. In the maternal karyotype, the inverted chromosome was identicalat the same level of resolution.

At this time, the proband was 25 years of age and his sisterwas 24. During this process, we also had the opportunity toexamine and interview the father and mother.

The father (II-13) of the proband (aged 71 at the time ofevaluation) had normal intelligence, was of normal heightand presented no evidence of behavioral problems uponpsychiatric interview. A strabismus was surgically correctedat age 28 and there had been treatment for glaucoma. He was

employed as a skilled laborer until his retirement at age 65and had been instrumental in maintaining a stable homeenvironment. One of the father's sisters (II- 18) was treatedmedically for reactive depression but we were unable to findany documentary evidence that she had experienced majorrecurrent depression.

The proband's mother (II-12), who was 67 at the time ofevaluation in 1989, had not been formally tested for intelli-gence, but upon interview appeared to have an IQ in thenormal or low normal range. Physically, she too was of shortstature (1.47 m in comparison to her daughter's 1.6 m), buther physical appearance was otherwise unremarkable. Shereported that she was infertile from age 23 to 33, but was

unable to provide information about possible pregnancywastage. She reported 11 siblings living and in good health,except for one brother (II-9) who had been repeatedly treatedfor depressive episodes with aggressivity. We were deniedthe opportunity to evaluate this uncle directly. The proband'smother denied that either of her own parents (who died atages 79 and 85, respectively) had behavioral problems or

serious health problems of any kind.In a brief clinical interview, this woman frequently inter-

jected irrelevant and digressive material and showed pressureof speech. She was combative towards her son and several

times was verbally restrained by her daughter. There was no

evidence of organic disorientation. She was suspicious bothof her son's motives and of the motives of clinical personnel.Although personally cooperative with her daughter, she wasresistant to the notion that her son required clinical evaluationor attention and notations from her son's school recordssuggested that this behavior was of long duration. Her ob-served social interactions were wooden and the proband'ssister reported that her mother had a very restricted socialnetwork. Indeed, the stability of the household reportedlywas maintained primarily by the father and daughter. Inaddition, the patient's mother displayed exaggerated anger inresponse to his behavior and overreacted to his inability tofunction normally. She had never been treated with antipsy-chotic medications and acknowledged no present or pastpsychiatric problem.We did not examine the two older sisters (born in 1958

and 1960, respectively) of the proband, but did interview andevaluate the younger sister (III-24). All siblings were report-edly in good health, with no apparent physical or mentalillness. Formal IQ testing was not available but on interviewintelligence in the younger sister (born in 1965) was aboveaverage, and she reported that her sisters all functionedeffectively in the home and workplace. Blood was drawnfrom the parents, the proband and his younger sister foradditional chromosomal study. Detailed evaluation of theinversion was defined by examination of high-resolution(400 to 600 bands) Giemsa banded chromosomes (Yunis1976). In the proband, 18 cells were examined, all of whichshowed an apparently balanced pericentric inversion ofchro-mosome 4, with breakpoints at p 15.2 and q 21.3 (Figure 2).An identical inverted chromosome was observed in nine cells

46,XY, inv(4)

(pl5. 2q21. 3)mat

-0

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Journal ofPsychiatry & Neuroscience

examined from the mother. At this level of resolution, a verysmall deletion or a very small duplication of chromosomalmaterial might have been missed (Tengstrom and Autio,1987). As both of the mother's parents were deceased andnone of her many siblings consented to cytogenetic evalu-ation, it was not possible to establish the origin ofthe invertedchromosome. In particular, we were unable to obtain consentfor cytogenetic evaluation or direct psychiatric interview inthe maternal uncle (II-9) with reported psychiatric symp-toms.

DISCUSSION

We report here a previously undescribed inversion ofchromosome 4 in a male with schizophrenia (DSM-III-R295.94) who also displayed very mild physical abnormalities.His mother, who showed symptoms of schizotypal personal-ity disorder (DSM-III-R 301.22), also carried this invertedchromosome. Strabismus was shared by the proband and hismentally and psychiatrically normal father. An examinedyounger sister had no chromosomal abnormality and goodmental functioning. A number of specific and general ques-tions are raised by these findings.

Is there a causal relationship between the chromosomalabnormality defined here and the mental illness seen in theproband?

A specific relationship between the inverted chromosomeand the phenotype of the proband cannot be defined withoutexamining additional cases. It is of course possible that theco-occurrence of psychosis and chromosomal abnormality issimply coincidental, but the presence of symptoms in bothknown carriers of the inverted chromosome makes this seemunlikely. Statistically, the particular inversion of chromo-some 4 reported here is unknown in either the psychiatric orthe genetic literature and thus must be rare (no higher than105). It is not possible to compute the conditional probabilityof a chance association between schizophrenia and inv 4(p15.2; q21.3), but it cannot in any case be greater than thepopulation prevalence of the inversion, which is two ordersofmagnitude lower than the population prevalence of schizo-phrenia. Also, the proband had never functioned at a levelcommensurate with his IQ score and had experienced asteadily worsening course from a poor baseline rather thanfrom good premorbid functioning. Although many individu-als suffering from schizophrenia have reasonably good pre-morbid functioning, others do not. We would submit that thisdistinction, both in our proband and in other cases with poorpremorbid function, suggests a congenital impairment inbrain function and points to an organic basis for the behav-ioral phenotype.A coincidental association between schizophrenia and inv

4 (pl5.2; q21.3) might be supported by the fact that themother, who carries the same inverted chromosome, is muchless severely impaired. We speculate that the sex of the

affected parent might be at issue here. Not only are femaleswith overt schizophrenia statistically less profoundly im-paired than males (whether for social or biological reasons),but it also suggested that penetrance of the severe phenotypeis reduced in females (Kendler 1987). Coincidental associa-tion would also be supported if a psychotic individual in thiskindred did not carry the inverted chromosome.

Direct examination of the apparently affected maternaluncle is obviously important to resolving this conundrum andefforts to achieve this are continuing. Even more compellingwould be the presence, in an unrelated individual, of anidentical or very similar inverted chromosome together withschizophrenic symptoms. By far the most common is the 4p-syndrome (Wolf-Hirschhorn syndrome), marked by severemental growth and motor retardation, as well as major physi-cal findings (Guthrie et al 1971). The critical missing seg-ment has been mapped to p15.2 by high resolution banding(Nahara et al 1987). Soukup et al (1974) and Francke et al(1977) report cases of proximal 4p- deletion in which mentaland growth retardation are moderate and physical findingsare reduced. More relevant to this case are the 13 reports ofpericentric inversion of chromosome 4 tabulated by Rivas etal (1987). In some ofthese cases there is considerable impair-ment of mental function and, in others, severe physical ab-normalities. In two kindreds (Baccichetti et al (1982), thereare several cases of apparently identical inv 4 (p15.2q1 1), arearrangement considerably smaller but fully encompassedby the one we describe here. In these kindreds, carriers hadmild or no mental retardation and microcephaly. In none ofthese reports is there any mention of behavioral status. How-ever, Schinzel (1984), in his Catalogue of Unbalanced Chro-mosome A berrations in Man, notes that many patients withinverted or ring autosomes show mild physical abnormali-ties, moderate mental retardation and psychotic behavior,including impulsive aggression. Although it is a caveat thatany chromosomal abnormality, whether euploid or aneu-ploid, carries an increased risk of mental retardation and/ormental illness, as compared to the general population(Hamerton 1971; Price et al 1976; Axelson and Wahlstrom1984), it is striking that certain relatively common chromo-somal abnormalities [i.e., Klinefelter's syndrome (47,XXY)]show a strong association with schizophrenia (Crow 1988),while others [i.e., Down's syndrome (47,+21) or Turner'ssyndrome (45,XO)] do not (Hamerton 1971; Price et al 1976).

What can this case tell us about psychiatric nosology ?

According to DSM-III-R, the differential diagnosis ofpsychotic symptoms instructs that, once an organic factorwhich precipitated or maintains the disorder has been identi-fied, the disorder is referred to the "organic" decision tree,and a diagnosis of schizophrenia is precluded. This case, andmany others like it, illustrates the difficulty of derivingappropriate generalizations from specific cases. On the onehand, we make progress in understanding schizophrenia byidentifying additional specific causes of schizophrenia-like

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psychosis and adding those etiologies to the (now very long)differential diagnosis of the "group of the schizophrenias"(Davison and Bagley 1969; Slater et al 1963; Propping 1983;Crow 1988; Bassett 1992). On the other hand, it is then statedby some that such a case was never schizophrenia at all andthat we have learned nothing about the etiology of thatimportant disease. This situation was aptly summarized byKay (1963), in the following words: "had the organic diag-nosis not been reached independently of the psychiatricsymptomatology, most of the cases [now identified by etiol-ogy] would have been regarded as indubitably schizo-phrenic". To take this point to its logical extreme, manyauthorities agree that there is an important heritable compo-nent in schizophrenia (Gottesman and Shields 1982; Kendler1987), even when all the known organic cases are excluded.If this is so, despite the fact that we do not know the genes

responsible or the mode of inheritance, there is an inescap-able physical and therefore "organic" basis for the diagnosis;we simply do not yet know its nature.

Is there a relationship between this case and the morecommon, as yet undifferentiated, diagnosis ofschizophrenia?

In this particular case, it is perhaps noteworthy that a

diagnosis was reached through a consultation for geneticcounselling and not as a consequence of routine evaluationand treatment. For obvious reasons, when genetic counsel-ling is requested, efforts to arrive at a specific diagnosis are

often redoubled and in this particular case a successful diag-nosis allowed us to tell the consultant that since she was nota carrier, and there was no risk of transmitting the invertedchromosome to her offspring. We also explained that it wasnot possible to evaluate the relationship between the chromo-somal abnormality and schizophrenia on the basis of a singledefined case. This does not, of course, mean that a karyotypeshould be routinely ordered for every case of "schizophre-nia". In fact, the clinical indications seen in this kindredconfirm appropriate guidelines, similar to those which havebeen suggested previously for general medical genetics(Hamerton 1971). Specifically: 1. the proband had never

functioned well, suggesting the possibility of a congenitalproblem; 2. the proband had mild physical findings and a

level of intellectual functioning decidedly lower than that ofhis siblings; and 3. there was at least one other relative withsome physical findings and with some psychiatric disability.Nonetheless, as our ability to identify small chromosomalrearrangements improves (Yunis 1976; Axelson andWahlstrom 1984; Tengstrom and Autio 1987), we are certainto identify additional specific chromosomal abnormalities inpatients diagnosed as suffering from schizophrenia.

Does this case have implications for linkage studies offamilial schizophrenia?

In recent years, there has been considerable emphasis on

the possibility that cytogenetic findings might suggest can-

didate regions in the search for genes which predispose toschizophrenia and other psychiatric illnesses. In medicalgenetics, this approach has indeed provided clues to thechromosomal localization of genes for familial retinoblas-toma (Francke 1976), cystic fibrosis (Young et al 1984),tuberous sclerosis (Clark et al 1988) and a variety of othersingle gene disorders. In 1988, Bassett et al reported anunbalanced structural abnormality of chromosome 5cosegregating with schizophrenia in an uncle-nephew pair;there was no evidence for psychiatric illness in any othermembers of the kindred. There have now been over a dozenattempts to map a general susceptibility locus for schizophre-nia to this region of chromosome 5 (reviewed in McGuffinet al 1991); in all but one case, the findings have beenunequivocally negative (Sherrington et al 1988). At best, thishas been a costly and disappointing exercise and, at worst, ithas created extreme skepticism about the appropriateness ofattempting to link psychiatry and molecular genetics (Owen1992).

In a recent review of autosomal anomalies presenting as"schizophrenia" or psychosis, Bassett (1992) proposed op-erational criteria for assessing the relevance of a particularchromosomal abnormality with respect to localization, vialinkage analysis, of putative major genes for schizophrenia.Of the 21 cases tabulated by Bassett (1992), five received ascore of six or greater (on a 12 point score) and only one wasrated at eight. Applying these criteria, the present case wouldscore at least six of 12.

Should we then turn to chromosome 4 as a candidateregion for a genetic linkage study of kindreds with schizo-phrenia? Certainly there are some interesting and plausiblegenes- the D5 dopamine receptor, quinoid dihydropteridinereductase, phosphoribosylaminoimidazole synthetase, inter-leukin 8, and the genes for several cellular growth factorsin the regions of the putative chromosomal breakpoints. Onemust then weight the cost of testing many kindreds againstthe likelihood that this too is simply another rare cause of"schizophrenia-like psychosis," important for differential di-agnosis but not generalizable. To return to the lessons ofmedical genetics, rare chromosomal abnormalities pointedthe way to the localization of the genes for cystic fibrosis andretinoblastoma (Francke 1976; Young et al 1984) becausethose disorders were already known to segregate in Mende-lian fashion and there was strong evidence for genetic homo-geneity in each case. In schizophrenia, neither of theseconditions is fulfilled: the mode of inheritance is unknownand the long history of progressive refinement of the differ-ential diagnosis of schizophrenia is consistent with bothphenotypic and etiological heterogeneity of the residue.

Barring homogeneity, some means of separating caseswith a distinct phenotype has been required. Cogent exam-ples are Lisch nodules in neurofibromatosis Type 1 (Riccardi1981), early age of onset and apparent autosomal dominantinheritance in familial Alzheimer's linked to chromosome 21(St. George-Hyslop et al 1987) and the presence of morning

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myoclonic jerks in a form of juvenile myoclonic epilepsynow known to be linked to chromosome 6 (Greenberg et al1989). Accordingly, progress toward understanding the ge-netic basis of susceptibility to schizophrenia might best bemade by simultaneously pursuing at least two quite differentstrategies. First, in those rare, very large kindreds in whichschizophrenia segregates in Mendelian or pseudo-Mendelianfashion, a full genome search is probably warranted, particu-larly in view of the development of highly efficient andinexpensive screening tools (Weissenbach et al 1992, forexample). Second, in smaller kindreds and in the generalpopulation of individuals suffering from schizophrenia, ef-forts to identify robust intermediate phenotypes should beincreased with particular attention to segregation in kindredsand affected relative pairs. A number of viable candidatetraits - eye tracking abnormalities, alterations of cerebralmetabolism, aberrations in cognitive processing, quantitativeEEG patterns, to name a few- have already been reportedin patients, but few have been studied in families. Not onlycan these traits help to define subpopulations which might bemore likely to share common genetic vulnerabilities, but theyalso hold promise for pinpointing the presence of suscepti-bility genes in persons who do not now, and who may never,fully express the disorder.

In summary, we report here the identification of a pre-viously undescribed abnormality of chromosome 4 in a pro-band with schizophrenia and in his mother who hassymptoms of schizotypal personality disorder. This case, andothers like it, have complex implications for clinical genetics,psychiatric nosology and the molecular investigations ofgenes conferring susceptibility to other cases of schizophre-nia.

ACKNOWLEDGEMENTS

We thank Helene Scarpelli, O.M.T.Q, for excellent technicalassistance and Herta Guttman, M.D., for encouraging theconcept of genetic counselling for patients and families withpsychiatric illness. This study was supported in part by aGrant-in-Aid from the Allen Memorial Advancement Fund.

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