Study of Behavioral Phenotypes: Goals andMethodological Considerations

Jo-Anne Finegan*Psychology Department, The Hospital for Sick Children, Toronto, Canada

The study of behavioral phenotypes associ-ated with genetic syndromes has gained in-creasing momentum over the past two de-cades. In this paper, the definition of behav-ioral phenotypes is presented and thecomplexities and obstacles to progress inthis field are summarized. Also describedare the goals of such investigations, includ-ing the need for syndrome delineation, pro-vision of guidance for clinical management,contributions to understanding brain-behavior relations, advancements in devel-opmental theory, and gaining understand-ing of the genetic bases of behavior. Meth-odological issues addressed in relation tosuch goals include the need for cross-disciplinary collaboration, concerns regard-ing sampling methods and comparisongroup selection, and developmental consid-erations. The complexity of cognitive abili-ties, the limitations of existing tests andmeasures, and ways of approaching thestudy of behavior are discussed. A final com-ment concerns the potential risks of re-search in behavioral phenotypes. Am. J.Med. Genet. (Neuropsychiatr. Genet.) 81:148–155, 1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: behavioral phenotypes; cog-nition; behavior; psychopa-thology; syndromes; mentalretardation; development

INTRODUCTIONUntil recently, the field of dysmorphology has con-

cerned itself almost exclusively with the delineation ofphysical phenotypes and their underlying pathogeneticmechanisms. Even the more complete of the dysmor-

phology textbooks has paid little attention to the cog-nitive or behavioral features of the various genetic con-ditions. Due to recent efforts to extend syndrome char-acterization into the realm of cognition and behavior,the field of ‘‘behavioral phenotypes’’ has come into itsown and the Society for the Study of Behavioral Phe-notypes has been established.1

A variety of developmental and psychological char-acteristics can form the behavioral phenotype. In thisfield, the term ‘‘behavior’’ is used in two ways. In itsgeneral application, it is used to refer to a broad rangeof human functioning including cognitive, language, so-cial characteristics, behavior (e.g., activity level), be-havior problems (e.g., hyperactivity), and psychopa-thology (e.g., attention deficit hyperactivity disorder).More specifically, the term refers to behavior in its ownright as distinguished from cognition. Typically, thegeneral or specific use can be gleaned from context.

Although it is acknowledged that some aspects of abehavioral phenotype are genetically determined, it isemphasized that a host of other influences, includingboth developmental and environmental considerations,also operate to create the observed outcome [O’Brienand Yule, 1995a].

Knowledge regarding the behavioral phenotype as-sociated with a particular syndrome allows a child’sbehavior to be anticipated [Finegan et al., 1994]. Dis-cussion has surrounded the question of how consistentthese patterns of behavior must be, however, to be con-sidered part of the behavioral phenotype. The conser-vative view is that the behavioral characteristic mustbe consistently associated with a condition [Flint andYule, 1994] or must be so common as to be the rule[O’Brien and Yule, 1995a]. The liberal view is that thebehavioral characteristic must simply have a predelic-tion [Einfeld and Hall, 1992] or a heightened probabil-ity or likelihood [Dykens, 1995a] to be associated witha particular condition. In dysmorphology, the widelyapplied concept of variability of expression means thatindividuals with the same syndrome will not expressthe same abnormality to the same extent [Jones, 1997].For example, supravalvular aortic stenosis is associ-ated with William syndrome, but it is understood thatthis cardiac anomaly is not seen in all cases. As behav-

Contract grant sponsors: The Laidlaw Foundation, The OntarioMental Health Foundation, The Medical Research Council ofCanada, The Harry E. Foster Foundation.

*Correspondence to: Jo-Anne Finegan, Department of Psychol-ogy, The Hospital for Sick Children, 555 University Avenue, To-ronto, Canada M5G 1X8. E-mail: jo-anne.finegan@mailhub.sickkids.on.ca

Received 1 July 1997; Revised 20 October 1997

1Information on the Society for the Study of Behavioral Pheno-types may be obtained from SSBP, 2nd floor, Douglas House, 18bTrumpington Road, Cambridge, UK CB2 2AH.

American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:148–155 (1998)

© 1998 Wiley-Liss, Inc.

ioral researchers become increasingly comfortable withthe concept of variability, debate will diminish regard-ing the inclusion or exclusion or frequency of a particu-lar behavioral characteristic in relation to the behav-ioral phenotype.

The field of behavioral phenotypes has evolvedslowly. The study of children with syndromes com-monly is the study of children with mental retardation,a group for whom care and concern is not a high prior-ity in our society. Research in this area has to take itsplace behind that of other more fashionable topics. Inaddition, behavioral research is perceived by many ofour laboratory research colleagues as having insuffi-cient rigor. Consequently, attempts to study the behav-ioral phenotypes of children with syndromes must con-tend with the relative disinterest common to the studyof behavioral aspects of disease conditions in general.

Probably the most significant factor constraining re-search progress in behavioral phenotypes has been thefact that many psychologists working in the field ofmental retardation have not kept pace with advancesin genetics [Dykens, 1995a, 1996]. As a consequence,many have continued to study groups with heteroge-neous causes for their mental retardation. Grossly out-dated notions are being applied, such as the compari-son of children with ‘‘organic’’ versus ‘‘nonorganic’’ con-ditions. An ‘‘organic group’’ might be comprised of thosewith Down syndrome, chromosome deletions, meta-bolic diseases, and so on. The ‘‘nonorganic’’ group mayinclude those for whom there has been no specific rea-son to account for their mental retardation.

In much of the existing research, it has been typicalto form research samples based on the degree of mentalretardation rather than on etiology [Hodapp andDykens, 1994; Zigler and Hodapp, 1986, 1991]. Burackand his colleagues, however, have convincingly arguedthe case for studying samples of children with specificcauses for their mental retardation [Burack, 1990;Burack, et al., 1988; Hodapp et al., 1990], insisting thatinformation currently arising from precision in etio-logic classification is proving to enhance research andintervention in the field. Although it is critical to con-sider the degree of mental retardation in studies ofbehavioral phenotypes, level of impairment is inad-equate as a basis for classification.

In the following section, the goals of research in be-havioral phenotypes are presented and discussedbriefly.

Studies of Behavioral Phenotypes: Goals

Research in behavioral phenotypes has at least fivemain clinical and theoretical goals.

Syndrome delineation. In behavioral science, asin other areas of science, initial research efforts may bedirected at simple description of phenomena, therebyproviding a basis for hypothesis-driven research. Inthis area, the first goal is to characterize the behavioralphenotype of the various syndromes. Although thesetypes of studies may be trivialized as being merely de-scriptive, they are critical because there is a need tounderstand more about these individuals in their ownright. Because so little is known, there is an obligation

to be as interested in behavioral development as inphysical development. Although studies of largesamples are desirable, well-selected case reports de-scribing behavioral phenotypes are as valuable as thecontributions made by case reports of physical pheno-types.

Much of what has been written about the behavioralfeatures of specific genetic conditions is outdated andinaccurate. As in the literature on physical phenotypes,it is typical for reports to present the relatively moreextreme cases. There is a responsibility, then, to char-acterize behavioral phenotypes more accurately. Todate, psychological research has been conducted onetiologically distinct groups, such as those with Downsyndrome [e.g., Cicchetti and Beeghly, 1990], Turnersyndrome [e.g., McCauley et al., 1987; Pennington etal., 1985], Fragile-X syndrome [e.g., Dykens et al.,1989; Dykens, 1995b; Freund et al., 1993; Hagerman,et al., 1989], Prader-Willi syndrome [Clarke et al.,1989; Dykens, et al., 1992a,b], Sotos syndrome [Rutterand Cole, 1991; Finegan et al., 1994], and Williamssyndrome [Bellugi et al., 1992]. The findings from stud-ies of these distinct groups of children have enhancedour understanding of typical and atypical developmentby identifying cognitive and behavioral patterns thatcharacterize each syndrome. Surprisingly little isknown about children with other syndromes, however.

Revealing intrasyndrome variability. An ap-preciation of intrasyndrome variability is importantboth to understand the range of phenotypic expressionand to preclude the promulgation of inaccurate infor-mation and the formation of stereotypes. For example,initial research on vocabulary and grammar in peoplewith Williams syndrome led to the view that languagewas ‘‘spared.’’ More recent and detailed studies oflarger samples, however, have revealed delayed devel-opment in these aspects of language [e.g., Karmiloff-Smith et al., 1997; Mervis et al., in press]. Thus, char-acterization of within-syndrome variability requiresobservations from large samples before conclusions aredrawn.

Understanding intersyndrome similarities anddifferences. Comparisons between specific syn-drome groups permits an understanding of the com-mon and unique features of each condition. As an ex-ample, to examine more systematically the anecdotalreports of behavior problems of children with Sotossyndrome, we studied rates of behavior problems usinga standardized questionnaire [Finegan et al., 1994].Rates of behavior problems in children with Sotos syn-drome were then compared with rates in children withother overgrowth conditions of known and unknowndiagnoses. The findings revealed that although chil-dren with Sotos syndrome had a high rate of clinicallysignificant problems, the rate was not higher than thatobserved for children in the comparison group. Thus, ahigh rate of behavior problems is observed in childrenwith overgrowth syndromes in general, and is notuniquely associated with Sotos syndrome.

Clinical management and prevention. The ex-amination of characteristic behavioral phenotypes inindividuals with genetic syndromes has implicationsfor counseling parents and for early intervention. A

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clearer understanding of the behavioral associations ofspecific syndromes may suggest that particular thera-peutic interventions are required. For instance, shouldit be revealed that behavior disturbance is a syndromecharacteristic, this information could be imparted toparents in an effort to minimize their sense of helpless-ness, failure, and guilt.

Knowledge about the developmental manifestationsof specific disorders permits identification of areas thatwarrant close monitoring for early signs of deviationfrom the typical developmental path. By so doing, pro-active identification can allow for early intervention.For example, prospective follow-up of infants with pre-natally identified sex chromosome trisomies has shownthat expressive language is delayed, suggesting thatthese children should be referred early for languageintervention. [Finegan et al., 1996]. Awareness of thebehavioral phenotype also leads to specific treatmentrecommendations. Girls with 47, XXX syndrome andwho have reading difficulties [Finegan and Barnes,1997] have shown good response to specific reading re-mediation programmes (i.e., systematic phonics train-ing), and thus are as amenable to treatment as childrenwith similar reading problems without this genetic con-dition.

Understanding brain-behavior relations. Theatypical cognitive and language profiles seen in chil-dren with syndromes permits the development of hy-potheses regarding brain structure and function. Forexample, the core cognitive deficits underlying thereading impairments of three girls with prenatallyidentified 47, XXX have been examined [Finegan andBarnes, 1997]. All three had impairments in phonologi-cal processing, that is, in the ability to consciously ac-cess the speech sounds in words. Neuroimaging studieshave revealed an increased incidence of symmetry inthe region of the planum temporale and parietooccipi-tal cortex in brains of individuals with dyslexia [Hyndand Semrud-Clikeman, 1989]. If deficits in phonologi-cal processing are replicated in a larger sample of girlswith 47, XXX, it might be hypothesized that an extra Xchromosome in females may affect integrity in thesebrain regions. Such findings could guide hypothesis-driven studies of brain-behavior relations. Questionsconcerning the role of an additional X chromosome forbrain development could be addressed by specifyingthese brain regions for examination by neuroimagingtechniques.

Contribution to developmental theory. Studiesin the field of behavioral phenotypes provide an oppor-tunity to answer larger questions about normal andatypical development.

Studies of aetiologically distinct groups of childrenwill help to provide data relevant to theories aboutwhat might be delayed and what might be different inretarded development [Burack et al., 1988, 1990]. The‘‘delay versus difference’’ theories of mental retarda-tion posit that specific groups of children may showdelays in development, whereas others may showunique differences. Psychologists studying develop-ment in typical children may have difficulty unravel-ling causal relations among abilities that emerge si-multaneously. The opportunity to study development

‘‘in slow motion’’ permits the link between chronologi-cal and mental age to be disentangled, leading to moreprecise analysis of sequences of developmental stages[Cicchetti, 1990].

Even in a specific group, both delays and differencesin development may be observed. For example, system-atic longitudinal study of children with Williams syn-drome [Mervis and Bertrand, 1998] has shown thatsome aspects of early language acquisition, such as thedevelopment of grammar, are delayed. Other aspects ofearly language acquisition in this group are different,however. For example, typically developing infants andthose with mental retardation associated with Downsyndrome, point to objects before they label them. Incontrast, those with Williams syndrome label objectsbefore they point. By illuminating the alternate path,this type of research challenges what has been believedto be a universal in early language development (i.e.,pointing before labelling).

Understanding the genetic bases of behavior.Molecular techniques are being used to identify chro-mosome microdeletions and permit genes to be linkedto specific psychological characteristics. For example,one recent study showed that some individuals withsupravalvular aortic stenosis associated with microde-letions at 7q11.23 have deficits in visuospatial con-struction [Frangiskakis et al., 1996]. Careful charac-terization of behavioral phenotypes will be the essen-tial groundwork for the emerging field of ‘‘genotype-phenotype correlations.’’

Methodological Considerations

Methodological issues concerning research in behav-ioral phenotypes are beginning to be identified. A feware presented here, with the hope that their recogni-tion may help researchers to avoid some of the moreobvious pitfalls and become more critical readers of theexisting literature.

Collaboration. Studies in the field of behavioralphenotypes are necessarily collaborative. For psycholo-gists, the need to work with clinical geneticists is em-phasized, particularly for diagnostic confirmation. Psy-chologists often are content to accept diagnoses in amedical record at face value, although these commonlyare made by nongeneticists and frequently are incor-rect.

Similarly, geneticists must conduct research in be-havioral phenotypes with psychologists who are awareof the complexity within various domains of psychologi-cal functioning, familiar with the optimal methods ofmeasurement, and skilled in assessing children whomay be difficult to test.

Geneticists looking for a psychologist collaboratorshould ensure that the psychologist not only has therequisite research skills, but also the certificationwhich will enable him or her to take responsibility forthe clinical issues that inevitably will arise. Parentswho volunteer for research projects quite understand-ably have their own concerns. Parents’ conscious or un-conscious motives for participation in a research proj-ect may be to develop a fuller understanding of theirchild, to be advised about the problems that they are

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facing, and to obtain information about the optimal in-terventions. Consequently, research in this field nevercan be simply ‘‘basic’’ research because of the partici-pants’ ongoing need for information and intervention.It is critical to find a balance between conducting theresearch project in the most efficient way possible,while acknowledging and satisfying the parents’ needs.

The behavior of individuals with syndromes can beextremely taxing in the testing situation and the psy-chologist must have the skills needed to manage be-havior seen as interfering during assessment. Indi-viduals with mental retardation are difficult to test be-cause of diminished motivation, inattention, lowexpectation for success, and approval-seeking behavior[see review by Zigler and Burack, 1989], so a repertoireof behavior management skills is needed in order toobtain an accurate picture of the individual’s abilities.

Ascertainment biases. Investigators must beaware of the implications of their sampling method [seediscussion by O’Brien and Yule, 1995b]. Ascertainmentthrough parent-run associations has the great advan-tage of putting the investigator in touch with a groupwho is proactive around research and highly moti-vated. Parents who are members of syndrome associa-tions are highly supportive of research, but member-ship in a particular syndrome association does notguarantee that each child actually has that diagnosis.The other caution in ascertaining samples through as-sociations is the impossibility of knowing about therepresentativeness of the sample. Association mem-bers who volunteer for research may or may not bethose who are more vocal, more distressed, or have chil-dren who are more severely handicapped or behavior-ally disturbed. It is not that these problems necessarilyexist, it is simply that data are unavailable on the rep-resentativeness of various syndrome association mem-bers.

Recruitment through specialty clinics may introducea different bias. For example, recruiting subjects for astudy on Williams syndrome through a cardiac clinicwill include a high proportion of those with supraval-vular aortic stenosis, and it is not yet known whetherthe presence of this cardiac anomaly is related to cog-nition or behavior in Williams syndrome. Subjects whohave been referred to psychology departments may beappealing because of the availability of psychologicalassessment findings, but it is probable that these indi-viduals have more apparent cognitive and/or behavior-al difficulties, which prompted the referral in the firstplace.

Given that there may not be a ‘‘perfect’’ recruitmentsource, the wisest course may be to cast the recruit-ment net widely. Note how the subjects were ascer-tained, and consider this as a potential source of biaswhen interpreting the findings.

The investigator ought to reflect on the informationprovided to parents regarding the study. When study-ing the cognitive profile of a sample, the investigatorcan be explicit with parents in describing the variablesunder investigation. If parents know that grammar orspatial memory is being studied, for example, it will notaffect the findings because the subjects will be testeddirectly for these abilities. In contrast, the investigator

needs to be cautious when talking to parents aboutquestions regarding behavior, which typically is evalu-ated using parent-report questionnaires. In this situa-tion, it is wise to be as general as possible. If subjectsare recruited using an advertisement in a parent news-letter that states that a study on attention deficit hy-peractivity disorder is being conducted, a biasedsample may be recruited because parents whose chil-dren are hyperactive, or who perceive their children asbeing hyperactive, may be more likely to come forward.

A related difficulty is that parents often will inter-pret behavior in terms of the current research question.For example, if the investigator informs parents thatthe study is about anxiety and asks parents to completequestionnaires that include anxiety scales, there likelywill be an over- or under-reporting of anxiety symp-toms. To avoid introducing bias, it is wise to be as gen-eral as possible, while acting in full conformance withethical principles of psychological research [AmericanPsychological Association, 1982].

Comparison groups. The recruitment of subjectsis fraught with a range of problems, and there are evengreater difficulties with the determination and ascer-tainment of comparison groups. With whom ought thegroup under investigation be compared?

Take rates of psychosis in people with velocardiofa-cial syndrome (VCF) as an illustration [e.g., Shprintzenet al., 1992]. If rates of psychosis in individuals withVCF are compared with rates in the general popula-tion, a differential rate may be observed. If rates arecompared with rates in a representative sample ofpeople with similar cognitive profiles [e.g., speech andlanguage disabilities with limited abstract reasoningas reported by Golding-Kushner et al., 1985] or withthose with other discrete syndromes, it is possible thatdifferential rates may or may not be observed. Canthere ever be enough comparison groups?

Comparing children with a specific syndrome only tochildren in the general population is of little value be-cause the children with syndromes will differ on manyother important variables as a consequence of differ-ences in level of intelligence, specific cognitive abilities(e.g., memory, language), and in environmental influ-ences.

Another approach is to compare those with a specificsyndrome to a heterogeneous but representativesample of individuals with mental retardation. A limi-tation of this approach is that such a comparison groupwill include those with a variety of conditions, manywith their own behavioral phenotypes. Furthermore, agroup comprised of children with no known diagnosis,really is a group for whom there is no known diagnosisyet.

A group with a specific syndrome may be comparedto groups with other discrete, diagnosed conditions.This allows for the detection of certain features thatmay occur across all disorders, permitting conclusionsthat the behaviors may be associated with the degree ofintellectual impairment or other explanations commonto both groups (e.g., see Sotos and overgrowth syn-dromes discussed above). Where a condition is found tohave a very different cognitive or behavioral profilefrom that of other conditions, there may be more evi-

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dence for a specific behavioral phenotype. This ap-proach has its merits but it also has its drawbacks. Forexample, how useful is it to know that children withWilliams syndrome differ from those with Down syn-drome in social relationships, given that people withthe two conditions differ so markedly in language com-petence? The main limitation of this design is that thenumber of comparison groups may be limitless.

As the foregoing suggests, a variety of convergingapproaches will need to be used to uncover the uniquecharacteristics associated with specific syndromes. Inthe initial phases of studying a syndrome, it may beprofitable to compare the index sample with the gen-eral population or with another specific syndrome.Thereafter, the appropriate control group will be sug-gested by the question being asked. Emerging findingswill permit more specific hypotheses and sharper ques-tions which will dictate further study using even morespecific comparison groups.

Developmental considerations. The develop-mental period selected for study has important impli-cations. In the past, reports have been published onsamples ranging from infancy to midlife. Collapsingacross this age range illuminates little, however, be-cause cohort effects will be operating. Children withsyndromes today are developing in a completely differ-ent environment than older individuals, and this needsto be taken into consideration. For example, most chil-dren with syndromes now are reared at home and haveparticipated in early intervention programs. It makeslittle sense to compare the group who have had inter-ventions with older individuals who did not experiencesuch advantages.

Another reason why collapsing across developmentalperiods is that certain behaviors may emerge or disap-pear at particular stages of development, so to includesubjects across too broad an age range may mask im-portant findings. Accordingly, it is best to concentrateon meaningful developmental periods such as infancy,preschool, school-age, adolescence, and adulthood.Moreover, there may be developmental ‘‘windows’’ dur-ing which particular behaviors may emerge. Behaviorproblems in children with Prader-Willi syndrome in-tensify over time [Dykens et al., 1992a] so that rates ofdifficulties may be underestimated if the sample in-cludes a disproportionate number of young subjects.

Both cross-sectional and longitudinal studies areneeded for complete characterization of behavioral phe-notypes. Cross-sectional studies, in which a sample ofindividuals with a specific syndrome are studied at onepoint in time, will help in the initial phases of investi-gation by describing a range of features and setting outhypotheses that merit further examination. Longitudi-nal studies, in which a sample is studied repeatedlyover time, will shed light on the changing shape of thebehavioral phenotype with maturation and develop-ment.

As mentioned above, the severity of the disabilitypresent is a key developmental factor to take into con-sideration [O’Brien and Yule, 1995a]. By this it ismeant that the rate and pattern of disorders canchange depending on the degree of intellectual retar-dation. In children with Sotos syndrome, the rate of

behavior problems is higher among those with moreimpaired intelligence [Finegan et al., 1994]. The coex-istence of low IQ scores and behavior problems does notimply a causal relation. Indeed, the two may be inde-pendent but their common association suggests thatseverity of the disability must be addressed. Moreover,disorders such as anxiety or depression may take onquite a different form in those with significant mentalretardation. Autistic-like features, for example, may berelatively rare in higher functioning children but maybe common among those with significant retardation.

Complexity of cognitive abilities. In studies ofcognition, it is not uncommon to see a complex cogni-tive ability reduced to a single variable. To take ‘‘lan-guage’’ as an example, verbal IQ score often is reportedas an index of language ability, but such a summarymeasure fails to take into consideration the complexityof language. A comprehensive examination of languagewill examine vocabulary, word-finding, word meaningor semantics, word structure or morphology (i.e., theability to use verb tenses, plurals, etc.), sentence for-mulation, fluency, listening comprehension, verbalconcept formation, pragmatics or the social use of lan-guage, and higher-order language processing, such asinferencing or the comprehension of figurative lan-guage. Cognitive abilities are multifactorial and com-plex, and although it may be practical and expedient toexamine just a few, it is important to be specific aboutwhat is being studied, and circumspect about the con-clusions that are drawn when only parts of a complexcognitive system, such as language, are studied.

Poor instrumentation. Available tests and in-struments do not always support research in behavior-al phenotypes. Norms for existing tests and measuresoften don’t extend into the lower ranges of ability thatcharacterize the groups of interest. Faced with a childwith moderate levels of impairment, investigators areunable to approach an understanding with the careand precision available for those in the higher ranges ofintelligence. There is enormous variability in the rangefalling below the lower test limits that could be cap-tured if the test norms extended down to that level.

Many standardized measures are not theoreticallygrounded and may not be useful for deconstructing or‘‘breaking apart’’ complex cognitive systems such aslanguage or memory. Measures that assess abilitiesglobally may mask variation within a cognitive do-main.

Psychopathology. Studies on behavioral pheno-types necessarily involve consideration of complex is-sues involving dual diagnosis, diagnostic overshadow-ing, and various approaches to examination of behaviordifficulties. These will be discussed next.

Dual diagnosis. Psychopathology in individualswith mental retardation, referred to those as having a‘‘dual diagnosis,’’ is common [Reiss et al., 1982]. Psy-chopathology is reported at a rate of 10% to 64% inindividuals with mental retardation, many timeshigher than that observed in the general population[Borthwick-Duffy and Eyman, 1990; Eaton and Meno-lascino, 1982; Gillberg et al., 1986; Matson and Barrett,1993; Reiss, 1985, 1990; Russell, 1985, 1988; Szyman-ski, 1980; Szymanski and Tanguay, 1980; Zigler and

152 Finegan

Hodapp, 1991]. Unfortunately, much of the epidemio-logical information concerning the coexistence of devel-opmental handicap and emotional/behavior distur-bance comes from populations of mixed etiology, so it isnot known which conditions are associated with highrates of, or are free from, specific mental health prob-lems. The study of behavior and its correlates in apopulation with developmental handicap of known eti-ology may illustrate an association with a particulartype of psychopathology [Zigler and Hodapp, 1991]. Todo this, efforts must be made to develop an understand-ing of specific cognitive and behavioral problems asso-ciated with specific syndromes. Surprisingly, no stud-ies on dual diagnosis have been undertaken on indi-viduals with any genetic syndrome [Dykens, 1996].

Diagnostic overshadowing. One reason for thislack of examination of psychopathology in individualswith syndromes arises from ‘‘diagnostic overshadow-ing,’’ which is the attribution of behavioral character-istics to mental retardation [Reiss et al., 1982]. Thecognitive impairments in those with mental retarda-tion are so salient that emotional and behavioral char-acteristics and problems may be overlooked [Alford andLocke, 1984; Reiss and Szyszko, 1983]. Depression,anxiety disorders, psychosis, and other coexisting con-ditions often go unrecognized and untreated. For ex-ample, an individual with a syndrome might collectevery issue of a particular weekly magazine and maybe preoccupied with this activity to the exclusion ofengaging with others socially. In this and other cases,it is typical for observed behaviors to be attributed tothe faulty cognitive mechanisms underlying intelli-gence. It needs to be learned, however, whether thisindividual has an obsessive compulsive disorder which,if treated successfully, may abate and permit expan-sion of interests and social relations. Behavioral andemotional problems may be treatable even though cog-nitive abilities may remain unchanged.

Approaches. Questions regarding behavior andpsychopathology may be approached from a number ofangles. One approach is to examine formal psychiatricdiagnoses. Although some children with syndromesmay manifest symptoms reflecting the usual range ofpsychopathology, most exhibit symptoms that are notusually regarded as symptoms of psychiatric disorder[O’Brien and Yule, 1995a]. Moreover, because of diffi-culties in language competence, there may be limita-tions in the expression of symptoms. Additional limi-tations of the ‘‘psychiatric approach’’ have been out-lined by Dykens [1995a].

Another approach is to look at behavior problemsusing the standardized methods of behavioral taxono-mies developed for children without syndromes andwhose intellectual abilities fall within the averagerange [e.g., Child Behavior Checklist; Achenbach,1991]. Behavior problem checklists have been devel-oped for use with nonhandicapped samples and capturethe range of behavior seen in the more typically devel-oping population. Data from these measures allow con-clusion about how children with a specific syndromediffer from those for whom normative data are avail-able. The information derived is in some respects lim-ited, however, because rating scales do not necessarily

determine a reliable diagnosis [Brunshaw and Szat-mari, 1988; Gutterman et al., 1987; Matson and Bar-rett, 1993; Young et al., 1987] Specifically, there arequestions about the nature of the observed behaviorand uncertainty regarding the need for intervention, asbehavior problem checklists may not necessarily maponto existing diagnostic systems [see discussions byBoyle and Jones, 1985; Edelbrock and Costello, 1988].In other words, scales tend to discriminate generalforms of psychopathology rather than specific diagnos-tic categories. For example, although a sample mayshow a high rate of anxiety, it is not known whether theindividuals have anxiety disorders. Moreover, mea-sures developed for children in the average range ofintelligence may not capture some of the unusual be-haviors seen in the various syndromes under investi-gation.

Another type of questionnaire has been developed foruse specifically with people with mental retardation,and the advantage of these questionnaires is that theyoften capture the maladaptive or aberrant behaviorsthat may be observed [e.g., Nisonger Child BehaviorRating Form, Tasse et al., 1996; see also Aman, 1991].Maladaptive behaviors are those that are socially un-pleasant, and present barriers to personal developmentand social integration into schools, families, commu-nity residences, and employment settings. Such behav-iors may include aggression, self-injurious, self-stimulating, and stereotyped behaviors, and pica[Gardner and Cole, 1993; Romanczyk and Kistner,1982; Thompson et al., 1993]. Because commonly useddiagnostic schemes do not address these behaviors, it isrecommended that formal measures of maladaptive be-havior be included in comprehensive assessments ofpsychopathology in individuals with mental retarda-tion [Borthwick, 1988]. Although investigators need tobe somewhat judicious in what they ask parents tocomplete, it is likely that questionnaires designed foruse in the normal and handicapped populations willneed to be included in the protocol.

Interpretive difficulties. Behavioral research inthis area has to grapple with the complexity of con-founding variables, including multiple influences onbehavioral outcome. When geneticists are consideringthe effects of genes on a physical phenotype, they canreasonably assume that a baby’s holoprosencephaly,cleft lip and palate, polydactyly and cardiac anomaly,arise from the same underlying cause. Psychologistslook to geneticists with envy because this way of think-ing is not applicable in the understanding of behavioralphenotypes, because at least three pathways may leadto an observed outcome. Some behaviors are geneti-cally determined, others are secondary phenomena re-sulting from variables unrelated to the syndrome, andyet others arise from genetic-environmental interac-tions.

In some conditions, behaviors such as depression,anxiety disorders, or obsessive compulsive disorder,may be genetically determined. That is, eventually itmay be shown that there is a direct effect of the gene(s)on behavior. In others, these behaviors may be set inmotion indirectly as a consequence of cognitive limita-

Behavioral Phenotypes 153

tions that lead to particular emotional/behavioral re-sponses.

In yet other individuals, psychological disturbancemight arise from social rejection and isolation whichare indirect consequences of the cognitive limitationsimposed by the syndrome. Discussions with peoplewith Williams syndrome, for example, often lead to atheme of social rejection. These individuals are wellaware of, and sensitive to, their social isolation frompeers. Particularly when peer relations rely increas-ingly on skill development in middle childhood, chil-dren with Williams and other syndromes, are left evenfurther behind and may become more and more sociallyisolated. The social circumstances in which individualswith syndromes develop may therefore lead secondari-ly to emotional and behavioral problems.

A third subset of individuals may experience suchdisorders as depression because of the genetic-environmental interaction. Genes may set the stage fora particular behavioral outcome (predisposition to-wards depression), and secondary effects may lower thethreshold for its expression even further (social rejec-tion and isolation). Finally, like any other individual,those with a syndrome may grow up in a dysfunctionalfamily, a well-known risk factor for behavioral distur-bance [Goodyer, 1990]. Social isolation and family dys-function are but two of many ‘‘nonsyndromic’’ factorswhich could interact with the affected individual’s ge-netic predisposition and compromised cognitive abilityto lead to psychological compromise. All must be takeninto account in disentangling genetic and nongeneticeffects on outcome.

Comment

Potential risks in the investigation of behavioral phe-notypes ought to be considered. Of concern is the pos-sibility of accepting the inevitability of cognitive im-pairment or behavior problems in a particular syn-drome. In so doing, there may be failure to providemitigating interventions and treatments. In this way,the expectation of difficulties may contribute to a self-fulfilling prophecy. Moreover, there is the possibility ofadditional stigmatization by the expectation of cogni-tive and behavioral difficulties. In the absence of com-prehensive and accurate information about behavioralphenotypes, genetic counselling decisions may be basedon inadequate data. These risks must be kept firmly inmind.

ACKNOWLEDGMENTS

Terri Sloss and Marcia Barnes helped to clarifymany ideas, and Pamela Bolan, Helen Hughes, MaryLou Smith, and Anne Summers made helpful com-ments on earlier versions of this manuscript. Personalawards and/or operating funds have been received fromThe Laidlaw Foundation, The Ontario Mental HealthFoundation, The Medical Research Council of Canada,and The Harry E. Foster Foundation. Earlier versionsof this paper were presented at the Eastern Canadaand New England Clinical Genetics Conference, Ot-tawa, June 7, 1996, and the American Society of Hu-man Genetics, San Francisco, October 30, 1996.

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