American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:235–240 (1998)
Behavioral Phenotypes: Conceptual and
Methodological Issues
Jonathan Flint*
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom
Specific behavioral patterns associated
with chromosomal and genetic disorders
are being recognized more frequently. The
hope is that the demonstration of a behavioral phenotype with a particular syndrome
may lead to the isolation of the behavior’s
genetic determinants. Three issues are considered here: the problem of defining a behavioral phenotype, the difficulty of demonstrating the existence of a behavioral phenotype, and the likelihood of characterizing
etiologically important genes. Although
there are many impediments to success, the
value of recognizing behavioral phenotypes
within a diagnostic syndrome is emphasized, and examples are given of how this
may lead to isolating behavioral genes. Am.
J. Med. Genet. (Neuropsychiatr. Genet.) 81:
235–240, 1998. © 1998 Wiley-Liss, Inc.
KEY WORDS: behavioral phenotype; aneuploidy; syndrome
INTRODUCTION
A behavioral phenotype refers to the specific and
characteristic behavioral repertoire exhibited by patients with a genetic or chromosomal disorder [Flint
and Yule, 1994]. The term raises a number of conceptual and methodological problems, three of which I will
deal with here. The first is how strict should the definition be. One of the best examples of a behavioral
phenotype is Lesch-Nyhan syndrome, in which a specific form of compulsive self-injurious behavior is found
so consistently that the diagnosis is called into doubt if
the behavior is absent [Christie et al., 1982; Anderson
and Ernst, 1994; Nyhan, 1976]. But if we required the
association between behavior and organic syndrome to
be so tight in every case, then almost no other disorder
would qualify as having a behavioral phenotype, and
we might well miss important observations about the
relationship between genes and behavior. For instance,
*Correspondence to: Jonathan Flint, Institute of Molecular
Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
E-mail: [email protected]
Received 1 July 1997; Revised 18 September 1997
© 1998 Wiley-Liss, Inc.
the behavioral phenotype of Williams syndrome is not
as well-established as that for Lesch-Nyhan syndrome.
Yet on the strength of its existence, it is claimed that a
gene for visuo-spatial construction has been cloned
[Frangiskakis et al., 1996].
The second issue is, how far must we go to demonstrate convincingly that a particular behavior is part of
a behavioral phenotype? The effort may be particularly
difficult for rare syndromes with small numbers of
cases and for odd behaviors which are hard to classify.
Below, I use the example of the behavior in fragile X
syndrome (FRAXA) to show just how daunting it can be
to establish the existence of a behavioral phenotype.
The difficulty of establishing a relationship between
a behavior and a syndrome prompts a third question:
what do we hope to achieve by defining and then demonstrating a behavioral phenotype? Is it in fact worth
the effort? When William Nyhan first proposed the
term ‘‘behavioral phenotype’’ [Nyhan, 1972], he intended it to convey the idea that the behavior was
chemically determined (a quarter of a century later the
phrase should read ‘‘genetically determined’’). Thus,
‘‘behavioral phenotype’’ implies a causal relationship
between organic lesion (genetic lesion) and behavior; it
is not simply ‘‘syndrome-specific behavior.’’ In the final
part of this commentary I will discuss how work on
animal behavior has given some grounds for believing
that there are genotype-phenotype correlations of the
sort implicit in the term ‘‘behavioral phenotype.’’ However, it is not yet clear whether the same can be said of
human studies.
Association Between Genetic Syndrome
and Behavior
The putative association between autism and
FRAXA provides important lessons about how associations between behavior and syndrome can be established. FRAXA is one of the best-characterized genetic
causes of mental retardation and is relatively common.
Yet finding a behavioral phenotype for FRAXA has
been far from easy. Three important lessons have
emerged from work on FRAXA that are of general relevance to the study of behavioral phenotypes.
The first is that the sample size needed to establish
an association at a statistically significant level is difficult to obtain (and is likely to be impossible for a rare
syndrome). Claims for an association between FRAXA
and autism, a childhood-onset psychiatric disorder di-
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Flint
agnosed on the basis of social abnormalities, deviant
language development, and stereotypic patterns of behavior, led to great interest in the possibility that
FRAXA might have a behavioral phenotype. A report
that perhaps 47% of autistic children had the FRAXA
anomaly [Gillberg and Wahlstrom, 1985] provoked a
lot of interest because it implied that a single gene on
the X chromosome could be a route to the biology of the
psychiatric condition. Although the figure is now
known to be lower than first suspected (studies using
well-validated diagnostic criteria put the figure at under 5% [Bailey et al., 1993]), it is still higher than the
population rate of 4 per 10,000. Does this mean that
FRAXA is associated with autism? Cohen et al. [1991]
attempted to answer this question by estimating the
joint occurrence of FRAXA and autism from the prevalence rates of the two disorders and then comparing it
to the observed prevalence. If the two conditions were
associated, then the observed joint occurrence would be
expected to exceed the number predicted from the
prevalence rates of the two conditions independently.
Conversely, if the conditions were independent, then 3
in 10,000,000 males would be both autistic and
FRAXA-positive, far less than the actual number. However, taking into account the confidence intervals
around the point estimates for the two conditions, as
few as 2 per million males could be jointly affected
[Fisch, 1992]. Fisch [1992] went on to argue from epi-
demiological analyses that mental retardation, a nonspecific consequence of FRAXA, may predispose to autism. His calculations did not rule out an association
between the two conditions, but they did show that the
sample sizes needed to detect a statistically significant
difference with reasonable power are large (Fisch
[1992] based his calculations on over 1,000 FRAXA patients and over 5,000 individuals with mental retardation).
To give an idea of how many cases may need to be
examined to find a behavioral phenotype, consider the
following situation. We want to know how many cases
to examine to be certain that a particular behavior is
significantly associated with a syndrome. We can set
up a null hypothesis that the true frequency is zero. We
then want to know at what frequency and with how
large a sample size the null hypothesis can be rejected
at a 5% level. Figure 1 provides an answer (the legend
explains how the graph was derived). We find that a
frequency of 15% would be needed to dismiss the null
hypothesis in a sample size of 20 or a frequency of 6%
in a sample size of 50. However, the numbers given in
Figure 1 are applicable in only the simplest situation.
The null hypothesis is more likely to be that the behavior exceeds a population prevalence (as in the case of
FRAXA) rather than zero, and if we are testing multiple behaviors then we need to use a more stringent
alpha level (Fig. 1 also gives information for an alpha
Fig. 1. The x-axis shows the number in a sample, and the y-axis the frequency of a behavioral measure. The graph shows the number in a sample
(x-axis) needed to reject the null hypothesis that the frequency observed (the frequency in this context would be of a behavior), as shown on the y-axis,
is not significantly different from zero. If the true occurrence is p, the probability of finding no events in n observations is: pr (0/n) 4 (1 − p)n. The data
then depart significantly from a true hit rate of p when pr (0/n) < a (where a is the chosen significance level). Setting a at 0.05, n log (l − p) < log 0.05.
This relationship is shown graphically for n from 10–1,000. My thanks to John Hewitt (Institute of Behavioral Genetics, Boulder) for suggesting this
approach.
Behavioral Phenotypes
level of 0.01). We may need sample sizes in the hundreds to detect behaviors that occur in less than a quarter of cases examined.
The second lesson to emerge from the study of
FRAXA and autism is that putative associations between behavior and syndrome could work in more than
one way. In addition to the hypothesis that FRAXA
could give rise independently to autism and mental
retardation, Cohen et al. [1991] suggested three other
possibilities. First, FRAXA could lead to autism, which
in turn gives rise to mental retardation, a very unlikely
scenario since more FRAXA males have retardation
than autism. Second, FRAXA could produce mental retardation, which in turn results in autism. Studies of
other medical conditions thought to be associated with
autism have provided evidence that the strength of the
association is strongly dependent on IQ level [Rutter et
al., 1994]. Third, FRAXA is associated with another
phenotype, which has some features related to autism,
a suggestion which now appears to be true, at least in
some instances. The behavioral phenotype of FRAXA
probably includes a deficit in social communication
that was detected by the autism diagnostic instruments. However, a rigorous demonstration of this required a flexible use of the behavioral measures, which
is the third point of importance to have emerged from
the work on the behavioral phenotype of FRAXA.
The third lesson is that behavioral phenotypes can be
missed if we have to use validated measures only. In a
controlled clinical study of young FRAXA males, Reiss
and Freund [1992] used a multi-item format that permitted researchers to produce a picture of the FRAXA
symptomatology. They found that a cluster of related
symptoms distinguished FRAXA males from controls,
i.e., symptoms that involved communication (e.g.,
speech production, nonverbal communication, and social play). What was different about FRAXA males’
communication? The deficit is probably in social interaction (as Cohen et al. [1991] suggested), manifested in
gaze avoidance, turning the body away during face-toface social interaction, and tactile defensiveness
[Borghgraef et al., 1987; Kerby and Dawson, 1994;
Bregman et al., 1988; Cohen et al., 1988; Wolff et al.,
1989]. Social avoidance, of the sort found in FRAXA, is
not the same as in autism, although the diagnostic instruments used for autism can pick it up.
Unusual behaviors for which there are no validated
measures can be found, e.g., in Smith-Magenis syndrome. Patients have brachycephaly with flat midface,
broad nasal bridge, short stature, brachydactyly, and
mental retardation. The syndrome arises from a deletion of 17p11.2 [Greenberg et al., 1991]. Direct observation of patients and parent interviews led Greenberg
et al. [1991] to the view that some unusual forms of
self-harm occurred in this syndrome. Not only would
patients bite their wrists and bang their heads, but
they also self-harmed in a more bizarre fashion: they
would pull out toe- and fingernails (onychotillomania),
and insert foreign bodies into various orifices (polyembolokoilomania) [Greenberg et al., 1991]. There are no
validated measures for such behavior.
237
Insights From Behavioral Genetic Studies
in Animals
Demonstrating an association between behavior and
syndrome is a difficult undertaking: so difficult that we
have to be certain that it is worthwhile. The hope is
that once an association has been established, a molecular characterization of the disorder will advance
our understanding of the biological basis of behavior.
Yet similar hopes have been disappointed in the past.
Most notably, work on the metabolic basis of inherited
forms of mental retardation has not revealed much
about the biology of intelligence.
However, there are data that give more grounds for
hope. First, there are instances of genetic lesions producing specific abnormalities in both animals and humans. An good example is the discovery that deficiency
of monoamine oxidase A (MAOA) leads to impulsive
aggression in humans and to aggressive behavior in
animals [Brunner et al., 1993; Cases et al., 1995]. The
mouse model thus provides a starting point for further
investigation of the biology of aggression. Other singlegene mouse mutants have also been noted to show abnormally aggressive behavior: in this way, pathways
involving calmodulin kinase and nitric oxide synthase
have been implicated [Nelson et al., 1995; Chen et al.,
1994]. Abnormal aggression is not the only behavioral
phenotype documented in mice: for instance, mice lacking the immediate early gene FosB were found to have
a markedly impaired ability to rear young [Brown et
al., 1996]. Having excluded anatomical and physiological defects (e.g., parturition and lactation were normal), Brown et al. [1996] found that the mutant mice
had a behavioral abnormality: the mothers did not
crouch over their pups as normal mice do, and made no
attempt to retrieve pups. Pups were usually found scattered around the cage and died from lack of maternal
care. FosB appears to be critical for the development of
adequate nurturing behavior.
Second, it turns out that the effects of single genes on
behavior are apparent not just in abnormal situations.
Analysis of traits in a number of animal and plant species has shown that less than 10 loci frequently explain
more than half the phenotypic variance of a trait (and
hence even larger proportions of the genetic variance
[Paterson et al., 1995]). The few extant quantitative
trait loci (QTL) studies of behavior show a similar picture: two QTL have been reported to account for 46% of
the genetic variance of alcohol preference in mice [Melo
et al., 1996]; three loci explain nearly 85% of the genetic variance of morphine preference in mice [Berrettini et al., 1994]; and three loci account for virtually all
the genetic variance of emotionality in mice [Flint et
al., 1995a].
Genotype-Phenotype Correlation Studies
in Humans
Genetic dissection of behavior would be impossible if
genetic lesions had nonspecific effects. Work on animals with single-gene mutations has shown that, at
least in some circumstances, this is not so. Furthermore, gene mapping experiments of behavioral traits
238
Flint
indicate that polygenic control may not involve as
many genes as first thought. These two observations
give hope that dissection of the genetic control of human behavior may be possible. They suggest that we
might find single-gene mutations underlying specific
behaviors in humans, and that it may be possible to use
a genetic approach to demonstrate a causal relation
between genetic lesions and behavior in humans.
Recent work on Williams syndrome provides a useful
example of successful genetic dissection of a behavioral
phenotype. Williams syndrome consists of growth retardation, infantile hypercalcemia, supraventricular
aortic stenosis, a characteristic facial appearance, and
mental retardation. There has been some interest in
the behavioral phenotype, with claims for specific linguistic and cognitive profiles [Udwin et al., 1987; Udwin and Yule, 1990; Wang et al., 1992; Crisco et al.,
1988; Bellugi et al., 1990; Tomc et al., 1990; Arnold et
al., 1985; Dilts et al., 1990]. Perhaps the best case can
be made for specific and characteristic cognitive deficits, where it has been shown that in contrast to relatively preserved linguistic skills, the visuo-perceptual
abilities of Williams syndrome children are lower than
those of controls. A few years ago, the molecular basis
of the syndrome was unknown, but proceeding from the
discovery of small deletions on chromosome 7q11.23
[Ewart et al., 1993], Frangiskakis et al. [1996] presented evidence that the gene LIM kinase I is responsible for the cognitive defect. Their approach is worth
considering in detail. They sought out individuals with
partial phenotypes, and they included within their phenotypic analysis a standardized measure of cognitive
abilities to measure what they termed a ‘‘Williams syndrome cognitive profile.’’ They discovered that families
with a mutation in the elastin gene might present with
supravalvular aortic stenosis and facial features, but
not with the cognitive profile of Williams syndrome.
However, two families had some facial features, supravalvular aortic stenosis, verbal ability, and short-term
memory similar to those of unaffected members, but
marked impairment of visuo-constructive skills. Molecular characterization of these individuals showed
that the chromosomal deletion was small (only 84 kb,
compared to >500 kb found in the majority of Williams
syndrome patients), which permitted the researchers
to isolate the candidate gene. Their approach thus
demonstrates the value of using a behavioral phenotype in the diagnostic profile, and shows how this can
lead to the identification of behavioral genes.
The example of Williams syndrome raises the question, how can we demonstrate that the odd behavior
shown by individuals with very rare syndromes (or
even individual cases) is directly related to a molecular
lesion? Although Williams syndrome is rare, it is still
possible to collect enough cases to test some hypotheses
about the existence of a behavioral phenotype. However, it may be that many cases of mental retardation
have a unique molecular lesion, and thus that gathering sufficient cases to establish a behavioral phenotype
is impossible. My own work has indicated that small
chromosomal deletions near the ends of chromosomes
are likely to be found in 7% of what is currently regarded as idiopathic mental retardation, and the ex-
tent and nature of the deletion vary between cases [Giraudeau et al., 1997; Flint et al., 1995b]. How can we
proceed?
Implication of the LIM-1 kinase gene in cognition
resulted from genetic analysis of unusual cases. Similarly, it may be possible to proceed directly from a behavioral phenotype to a gene. For instance, the child
shown in Figure 2 has a small telomeric deletion of
chromosome 22q. He has no physical abnormalities,
but he does have a specific cognitive profile that is
unique in his family. He has a deficit in expressive
language and reading skills (his verbal IQ is 50, while
his performance IQ is in the low normal range). Siblings and parents have neither the 22q deletion nor
cognitive deficit. We now know that he has a terminal
deletion of 130 kb and that this includes only 70 kb of
chromosome-unique DNA (the subtelomeric regions of
chromosomes contain large tracts of repetitive DNA)
[Wong et al., 1997]. Thus there is only a small region to
search to find a gene (or genes) that may be involved in
determining variation in verbal IQ.
Future Directions
I have highlighted the difficulties inherent in the
definition and ascertainment of behavioral phenotypes.
First, the syndromes in which behavioral phenotypes
occur are rare, and not all cases may manifest a specific
behavioral abnormality; consequently, ascertaining
sufficient cases to demonstrate a statistically significant association may not be possible. Second, while it is
essential to use a validated behavioral measure (and
that is unlikely to be available, particularly for such
traits as onychotillomania or polyembolokoilomania), if
the wrong measure is used, a behavioral phenotype
may be missed. Finding a behavioral phenotype is
therefore not a trivial exercise: there needs to be a good
reason to persist with its delineation.
There is a long tradition in neurospsychology of reporting detailed assessments of single patients with
lesions restricted to small regions of the brain. Such
research has been extremely fruitful in unravelling the
relationship between brain function and structure.
Fig. 2.
Patient N.T., age 12. No physical abnormalities were found.
Behavioral Phenotypes
239
Could a similar approach help explain the relationship
between gene and behavior? The examples I have presented here suggest that investigating behavioral phenotypes is a way to locate genes that influence behavior; this is a major justification for their study. In the
final part of this commentary I will consider how further progress can be achieved.
Four techniques would increase the chances of success for genetic approaches to the study of behavioral
phenotypes. The first is a screen of regions of monosomy. We now have a strategy to screen for subtelomeric deletions [Knight et al., 1997], but we do not yet
have a way to analyze the whole genome for monosomy.
The development of such a test would enable us to look
for small deletions that are much more likely to have
associated specific behavioral abnormalities. Such
cases would be the essential case material upon which
to base studies of the relationship between gene and
behavior. Second, we need a sophisticated battery of
neuropsychological and behavioral tests. Available assessment schedules are either too clinically oriented or
require a much higher level of functioning than is possessed by the majority of patients with chromosomal
abnormalities. Third, we need a transcript map so that
we can quickly identify the genes that are likely to be
affected by any deletion we find. Finally, we need a way
of deciding which genes are dosage-sensitive. Such
genes would then be candidates for genes responsible
for the behavioral phenotype. While a transcript map is
now being generated, the technology to identify dosagesensitive genes is not yet available. But once it is, we
could have in place a powerful way of finding the genetic determinants of behavior.
In conclusion, the delineation of behavioral phenotypes is a difficult enterprise, but that should not dissuade clinicians from undertaking it. Behavioral phenotypes may offer a unique approach to the identification of genes determining behavior and behavioral
abnormalities. Geneticists, and other clinicians dealing
with rare syndromes and chromosomal disorders, need
to recognize that behavior can be as much part of a
syndrome as facial dysmorphism. Delineation of a behavioral phenotype could then be the first step towards
the molecular characterization of behavior.
Brown JR, Ye H, Bronson RT, Dikkes P, Greenberg ME (1996): A defect in
nurturing in mice lacking the immediate early gene fosB. Cell 86:297–
309.
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