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The following information represents the most current information available from the National Institute of Health regarding the genetics of Tourette Syndrome.

Written by Dr. Alsobrook, Yale University School of Medicine
for the National Institute of Health

Phenotype: Tourette's syndrome (TS) has its onset before age 18 and is characterized by the involuntary, sudden, rapid, recurrent, nonrhythmic, and stereotyped occurrence of multiple motor and/or vocal tics. Tics typically involve the head and other parts of the body (torso, upper and lower limbs). Vocal tics include various sounds like clicks, grunts, barks, coughs, or words. Some investigators have expanded the phenotype also to include chronic motor or vocal tics (CT) and OCD [407-409], while others expand the phenotype even further to include ADHD, PD, conduct disorder, depression, dyslexia, stuttering, mania, obesity, and alcoholism [410]. Phenotypic definitions remain controversial and are an important consideration in the genetic analysis of TS [411-414]. No evidence on test-retest or interrater diagnostic reliability is available.

Epidemiology: Estimates of the prevalence (male:female ratio, if available) of TS in studies relying on identified treated cases were 0.046 in 10, 000 in Minnesota [415], 0.50 in 10, 000 (3.5:1) in North Dakota adults [416], and 5.2 in 10, 000 (9.3:1) in North Dakota juveniles [417]. School-based surveys [418] yield much higher estimates of 23.4 in 10, 000 (8:1). Community surveys have revealed prevalence rates of 2.9 in 10, 000 in Monroe County, NY [419], 0.7 in 10, 000 in New Zealand juveniles [420], and 4.3 in 10, 000 (1.6:1) in Israeli adolescents [421]. A population prevalence of 5 in 10, 000 therefore is commonly cited [422], and variability may represent methodological (including diagnostic) differences.

Family Studies:TS [423-430], CT [424, 431] and OCD [261, 427, 432-437] aggregate in the families of TS probands. While CT and OCD may be spectrum disorders that in some cases reflect a TS genotype, etiologic heterogeneity (including nongenetic causes) is likely [438]. Two early family studies that indirectly assessed first-degree relatives of TS probands in a national sample [423] and in consecutive clinical cases [424] found a recurrence risk of about 2 percent. A risk of 1.5 percent also was observed in relatives of twins assessed by telephone interviews [425], but subsequent studies that directly assessed relatives yielded much higher estimates. Risks of 18 percent [426], 21 percent [427], 27 percent [428], and 36 percent [429] for relatives of TS probands have been found in each of three large pedigrees. Including CT increased the recurrence risk to 46 percent [428], 30 percent [426], and 51 percent [429].

A family study in which all relatives were interviewed personally reported respective age-corrected risks of 8.7 percent for TS, 17.3 percent for CT, and 11.5 percent for OCD in first-degree relatives of TS probands, with no significant differences in the rates of these disorders in the relatives of male and female probands [430]. A nearly fivefold increase in risk for TS in males versus female relatives (15:3.4) and over a twofold difference in risk to OCD in female versus male relatives (15:7) of TS probands were observed [430]. Assuming a lifetime prevalence of 5 in 10, 000 and a lifetime recurrence risk of 8.7 percent for TS, the respective recurrence risk ratio for first-degree relatives is about 174.

Twin Studies: One twin study has been conducted, and the respective pairwise MZ and DZ concordance rates were 53 percent and 8 percent [425]. Twins were ascertained as pairs; thus, 50 probandwise concordance cannot be estimated.

Adoption Studies: No adoption data have been reported.

Mode of Inheritance: Segregation analysis of single pedigree or pedigree sets have supported transmission through an incompletely penetrant autosomal dominant major locus with variable sex- and age-specific penetrances [426-428, 439-442]. There is evidence of autosomal dominant transmission if the phenotype is defined as (a) TS only, (b) TS or CT, or (c)TS or CT or OCD [407, 426]. Two studies [440, 443] could not reject a multifactorial-polygenic model, and one [443] could not reject a mixed model of inheri-tance that combined an intermediate major locus and a small but non-negligible multifactorial background.

Evidence also has been found for semidominant or intermediate inheritance (higher penetrance in affected homozygotes than in heterozygotes) [443-445]. One possible explanation for discrepancies across studies is that dominant inheritance may have been falsely inferred because of the failure to account for assortitive mating [429, 446]. The rates of bilineality described previously appear greater than would be expected for a rare autosomal dominant disease. Modeling of assortitive mating in segregation analysis of TS [445] led to identification of a different model of major gene inheritance (intermediate or additive major locus) from that identified (dominant mg on locus) when random mating was assumed.

A recent study of nonbilineal pedigrees rejected pure multifactorial and single major locus models and found evidence of a mixed model of inheritance that combined an additive major locus with a multifactorial background [447]. It is unclear whether the multifactorial factor presents polygenic or shared additive environmental effects, but it did account for about 40 percent of the phenotypic variance.

In summary, the mode of inheritance for TS is likely complicated by locus heterogeneity and assortitive mating. Conflicting results may be attributable to methodological differences in family ascertainment, phenotypic definition, diagnostic assessment, and data analytic approaches, but they also may represent true differences among families. On the basis of these data, susceptibility to TS may be influenced by a major gene in some families and perhaps by multiple genes of small relative effect in others. The role of familial transmissible effects (environmental or additive genetic) is unclear.

Molecular Genetic Studies: The TS Genetic Consortium has pursued a total genomic search in 11 large families from the United States, Canada, the Netherlands, and Norway and tested over 600 genetic markers under the assumption of genetic homogeneity and incompletely penetrant autosomal dominant single major locus inheritance [448, 449]. Over 90 percent of the genome has been excluded [450]. Comings and colleagues [451] reported increased homozygosity for the D₃ receptor gene, but there has been at least one failure to replicate [452].

A role in linkage analysis has been excluded for several genes involved in catecholamine (D₁-D₅ receptors and DBH, DAT, TY, and TH genes) [453-457] and serotonin (5-HT1A receptor, tryptophan oxygenase) [458] pathways, under incompletely penetrant autosomal dominant or intermediate major locus models. There have been several reports describing chromosomal abnormalities in single TS patients, including a 9p deletion [459], an 18q deletion [460], t(7;18) translocation [461], and a 46 XY, t(3:8) (p21.3 q24.1) balanced translocation [462-464]. Although a positive multipoint lod score of 2.9 was initially obtained on 3p in several pedigrees [462], subsequent analyses using improved map data and additional markers led the authors to conclude that this region was not involved in the etiology of TS [464]. A YAC spanning the translocation breakpoint at 18q22.3 in the TS proband carrying the balanced t(7;18) translocation [461] was identified; among the limited number of relatives in the family studied, no one without the translocation was diagnosed with TS [465]. Co-segregation of the translocation with TS of course could be coincidental, especially given that the frequency of a carrier of a balanced translocation in the population is about 1 in 1, 000.

Finally, the TDT [49] was used in a family-based association study [466] to identify an association between a specific allele at the D₄ dopamine receptor locus and TS (p values varied from 0.004 to 0.001 across different disease definitions); linkage to this gene, albeit under restricted parametric assumptions, has been excluded in at least one large family [453]).

A recent report of earlier age at onset in maternally transmitted cases in a small number of families [467] led the authors to conclude that there could be a parent-of-origin effect on a putative TS gene. It was recommended that family data be re-examined separately for maternally and paternally transmitted cases. At least one failure to find a significant difference in age at onset between maternally and paternally transmitted TS cases was reported earlier [468].

Animal Studies: No relevant genetic studies using selectively bred, recombinant inbred, or transgenic animal strains and gene targeting (knock-out and knock-in techniques) have been reported.

The following article represents one of the best articles written thus far on the subject of Tourette Syndrome genetics.

The Genetics of Tourette Syndrome

Abstract

The familial nature of Tourette syndrome (TS) was first described by Georges Gilles de la Tourette in 1885. Formal investigations of TS since the 1970s have consistently demonstrated an increased risk for TS among relatives of patients with TS. Family studies, twin studies, and segregation analyses all indicate that TS has significant genetic determinants. The mode of transmission, while mildly controversial, is generally believed to be due to at least one major locus inherited either as an autosomal dominant trait with reduced penetrance, or as a trait with intermediate inheritance in which some heterozygotic persons manifest the disorder. There is evidence for a TS spectrum of symptoms that includes chronic tics and obsessive-compulsive disorder. Systematic genome linkage studies of TS are progressing. To date, however, no significant linkage findings exist, although the search has included many neurologically relevant candidate genes.

Introduction

The familial nature of Tourette syndrome (TS) was first described by Georges Gilles de la Tourette in 1885. However, it was not until the 1970s that studies by Eldridge et al1 and Shapiro et al formally demonstrated an increased frequency of positive family history for tics in families of TS patients. A 1980 family history study by Kidd et al³ was the first to present rates of TS and chronic tics (CTs) among relatives of TS probands. That early study combined TS and CTs into a single category and showed that the risk to relatives was significantly elevated over that expected by chance. In 1981, Pauls et al⁴ reanalyzed those data, as well as family history data collected from TS clinic patients, to demonstrate that: (1) the increased risk among relatives for TS and CTs was consistent across the two samples and higher than expected by chance alone; (2) CTs appeared to represent a variant expression of the syndrome; and (3) the patterns of occurrence of TS and CTs were consistent with vertical transmission within families.

Family History Studies

Six groups^5-10 subsequently reported results from genetic analyses of family history data in which specific transmission hypotheses were examined. All of these groups concluded that the pattern of transmission within families was consistent with a genetic hypothesis that postulated a single major locus to be responsible for susceptibility to TS and/or CTs. However, this was not the only hypothesis supported. Kidd and Pauls⁹ were unable to reject the hypothesis that transmission of the syndrome was consistent with the contribution of many genes, each having an equal and additive effect on expression of the disorder (a multifactorial polygenic model). Likewise, Comings et al6 could not reject a multifactorial polygenic model unless extended relatives were included in the analyses and the estimated population prevalence for TS and CTs was restricted to less than 75%.

Nevertheless, the authors of all the studies consistently concluded that the mode of inheritance best fitting the available data was one that included an underlying single major locus. Three of the studies^5,6,10 concluded that the most likely mode of inheritance for TS and/or CTs was autosomal dominant, with sex-specific penetrances.

All of the above studies relied on family history data for the analyses; ie, the diagnoses of relatives were based on information given by one, or at most two, informants per family with no direct evaluations. It has been demonstrated in studies of other neuropsychiatric disorders that family history data underestimate the true rates of illness as determined by direct assessment.^11,12 This was shown to be true for TS as well as CTs.^13,14

Estimating rates of illness by family history data alone is only one of a variety of reporting biases that lead to methodologic difficulties in many studies. Since these reporting biases can affect disease patterns within pedigrees, it is not surprising that the specific estimates of gene frequency and penetrances vary considerably among studies. Accurate estimates of these genetic model parameters are critical for genetic counseling and for genetic linkage analyses (discussed below).

Twin Studies

Twin studies also provide evidence for the importance of genetic factors in TS. Twin studies are based on the fact that monozygotic (MZ) twins are genetically identical and share nearly the same prenatal environment. Dizygotic (DZ) twins share, on average, 50% of their genes and also the same prenatal environment. If a disorder is determined by genes alone, MZ twins should be 100% concordant for the disorder and DZ twins should show a concordance rate of 50% or less. Anecdotal and incidental observations on DZ and MZ twins with TS show variation in age of onset and type and severity of symptoms between cotwins.^1,15-24 Taken together, a concordance rate of 50% to 70% for TS and 75% to 90% for TS and tics combined can be calculated for MZ TS twins.^2,20 For DZ TS twins, the concordance rates in both conditions are 10% for TS alone and 20% for TS and tics combined.^2,20

Environmental prenatal and postnatal factors may influence the expression of TS in individuals at risk for the disorder, explaining the absence of a 100% concordance rate for TS and/or tics in MZ twins.^25,26 For example, in one series, all the affected discordant MZ cotwins had a lower birth weight compared with the unaffected cotwins.²⁶ In another series of MZ twins who were concordant for TS and tics, the cotwin with the lowest birth weight consistently had the most severe symptoms.²⁵

A twin study by Price et al²⁰ demonstrated that the potentially hazardous effects of relying on family history data for diagnostic purposes may be present in twin studies as well. These researchers reported a concordance rate for TS of 53% for MZ twin pairs and 8% for DZ twin pairs. The data for this study were obtained by questionnaires and follow-up telephone interviews with the mothers of twins. The results were comparable to those reported in some of the studies discussed above.^5,6,10

Concordance rates for MZ twins can be interpreted as an estimate of penetrance if the underlying genetic mechanism is a single locus; thus, the reported concordance rate of 77%, when cotwins with either TS or CTs are considered to be affected, can be viewed as a penetrance of 77%. However, just as a number of possible reporting biases may affect the results of genetic analyses based on family history data, reporting biases may also affect the results in twin studies. As a follow-up to their 1985 investigation, Leckman and colleagues²⁶ recontacted all twin pairs and conducted personal interviews with each twin. The concordance rates estimated from personal interview data increased to 100% for MZ twins when cotwins with either TS or CTs were included as affected. Even for twins, the rates of illness can be underestimated if the investigator relies on historical data provided by an informant rather than on data collected by direct personal interview of the subject.

The TS Phenotypic Spectrum

Another major focus of TS genetic studies has been the delineation of the behavioral phenotype associated with the underlying genetic diathesis. Although a number of psychiatric and behavioral disorders have been hypothesized,²⁷ the strongest data concern obsessive-compulsive disorder (OCD). Recent results from several well-structured studies^7,26,28-30 have supported earlier findings, and it is generally accepted that, within families of TS individuals, the two disorders are etiologically related.

In addition, family study data indicate that OCD alone (ie, no current or past history of tics) may represent a variant expression of the disorder.^31-33 In a study by Leonard et al³¹ involving 54 consecutively admitted OCD probands, TS was an exclusionary criterion for enrollment. At follow-up 2 to 7 years later, 12% of the OCD probands had onset of TS. Pauls et al32 showed that the rate of tics (TS and CTs) among 466 relatives of 100 OCD probands was 4.6%, significantly higher than the rate of 1% seen among 113 control relatives. It is interesting to note that these data also suggest that not all OCD is related to TS, since it was more likely that a relative would have tics if the proband also had tics. If all cases of OCD were related to TS, then the rate of TS and CTs should have been the same among relatives of OCD probands with or without tics.

Segregation Analysis

Pauls and Leckman³⁴ examined the mode of inheritance of TS using complex segregation analysis to compare formal mathematical genetic models. Their experimental design also addressed the question of whether the occurrence of OCD within the families of TS probands was consistent with genetic transmission of TS, CTs, and/or OCD. While their overall conclusion that TS is inherited as an autosomal dominant condition was noteworthy, their findings regarding a TS phenotypic spectrum were even more remarkable. An autosomal dominant hypothesis was consistent with several affected categories, including: (1) relatives with only TS; (2) relatives with TS or CTs; and (3) relatives with TS, CTs, or OCD. The fact that the inclusion of OCD resulted in a significantly better fit with the observed data within families suggests that OCD is part of a genetically mediated TS spectrum. These data also suggested that, rather than a sex-specific frequency of the illness (limited only to TS or CTs), there may be a sex-specific expression of the illness, with OCD representing the part of the TS spectrum more frequently expressed in females. These findings were replicated in two independent samples. Eapen and coworkers³⁵ studied the families of 40 consecutive TS probands seen in a London clinic, and van de Wetering³⁶ studied the families of approximately 45 TS patients seen in Rotterdam. These two series resulted in strong statistical evidence that the pattern of transmission of TS, CTs with OCD, and OCD without tics was consistent with an autosomal dominant inheritance. The penetrances obtained for these two samples were remarkably similar to those reported above, ranging from 0.5 to 0.9 for males and 0.2 to 0.8 for females (depending on the diagnostic scheme used in the analyses). A third segregation analysis painted a more complex picture of TS inheritance. Hasstedt and colleagues³⁷ analyzed a single large TS kindred containing 182 family members. Affected status was assigned based on a point system that incorporated the TS symptom types, the number of tics reported and/or observed, and any obsessive-compulsive symptoms. Their study was a reanalysis of a pedigree for which prior analyses had rejected mendelian inheritance. The key difference in this second round of analyses was the incorporation of an assortative mating correlation in the genetic model. This was significant, since the rate of TS in spouses of the pedigree descendants was greater than that seen in the general population. The new results showed an intermediate mode of inheritance, with a penetrance of 0.28 in heterozygotes and 0.98 in homozygotes.

The reanalysis by Hasstedt and colleagues³⁷ is especially interesting in light of a significant finding of "bilineal transmission" of TS by Kurlan et al.³⁸ The frequency of transmission of TS from both maternal and paternal sides of the families of probands was determined by examining 39 high-density families (five or more affected relatives within three generations of the proband) and the families of 39 consecutively evaluated TS clinic probands. Diagnostic information was collected for all relatives within three generations of the proband; the presence of tics in relatives was confirmed by direct clinical examination of at least one member of the maternal side and one member of the paternal side.

The results of this study indicated that 33% of the high-density families and 15% of the consecutive-evaluation families showed bilineal transmission of TS. By including obsessive-compulsive behaviors in the affected status, the proportions were 41% for bilineal transmission in high-density families and 26% for bilineal transmission in the consecutive-evaluation families. No consanguinity was evident in any of the families. Therefore, if a single major locus contributes to TS susceptibility, homozygosity at such a locus is common among TS families. This investigation also demonstrated that the frequency of bilineal transmission is related to the severity of TS in the probands. An increased severity of symptoms among the affected offspring of two TS-affected parents was also reported by McMahon et al.³⁹

Taken together, these findings lend credence to a dose-effect model of TS, wherein an affected individual who is homozygous for a TS susceptibility allele is likely to be more severely affected than an affected individual who is heterozygous. Because linkage studies are critically dependent upon proper specification of the genetic model, it may be fruitful in future analyses of TS linkage data to include model parameters that reflect an additive gene-dosage effect. While these studies do differ in terms of the specific genetic model supported, they provide a strong rationale for ongoing genetic linkage studies.

Linkage Analysis

Genetic linkage studies provide what is arguably the most powerful method for confirming the conclusions of the family studies and segregation analyses described above. Linkage results, by definition, demonstrate the existence of a major genetic locus and help clarify the pattern of inheritance even in the absence of a known association between a biologic abnormality and a disorder. The objective of linkage analysis is to demonstrate that a distinct segment of DNA (ie, a DNA marker, with known chromosomal localization, that may or may not be an actual gene) cosegregates with a disease in a family. Genetic linkage is detectable if such a marker is sufficiently close to a locus that influences a disorder so that nonrandom segregation of alleles at the two loci results in an association among phenotypes within families. Thus, if it is possible to demonstrate genetic linkage between a locus for TS and a known-marker locus, the demonstration will provide convincing evidence of genes of major effect that contribute to the expression of TS. Once located, the genetic marker provides an extraordinarily powerful research tool for dissecting out the specific genetic defect, identifying the relevant environmental risk factors, and characterizing their interactions.

Advances in DNA technology have made it possible to detect many highly polymorphic genetic markers spanning the entire human genome. Extensive linkage mapping of all human chromosomes has resulted in the creation of several human genomic maps.^40,41 The application of these mapping techniques will help to clarify the genetic mechanisms of TS, OCD, and related behaviors through genetic linkage studies. Theoretical and empirical work suggests that, irrespective of problems of incomplete penetrance, linkage studies can identify the location and thereby verify the existence of the genetic loci that are important in the expression of these disorders.^42,43 However, multiple strategies need to be employed in the study of complex disorders (eg, TS) that do not exhibit mendelian patterns.

Recent developments in molecular biology have resulted in the cloning and analyzing of a large number of disease genes. In most cases, disease genes could be cloned because information was available concerning a specific biochemical defect (eg, a defect in the gene product or function). The strategy of identifying a disease gene by its known abnormal gene product or function is referred to as functional cloning.

For genetic diseases of unknown etiology, an alternative strategy called positional cloning is used to identify the responsible genes. Positional cloning begins with a positive linkage finding, allowing the localization of a susceptibility locus to a particular region of a chromosome. Subsequent steps involve narrowing down the chromosomal region from tens of millions of base pairs to tens of thousands. Through this method, the gene that confers susceptibility is eventually identified. The genes for Huntington's disease, Duchenne's muscular dystrophy, cystic fibrosis, neurofibromatosis type I, and fragile X syndrome have recently been identified by positional cloning methods. Clues to interesting chromosomal regions may also come from cytogenetic studies, where chromosomal rearrangements may be associated with a disorder. Although some indication exists that specific brain structures are involved in TS, the etiology is still unknown. In addition, no biologic markers are currently available. In the absence of specific abnormal gene products and candidate brain regions, several strategies must be used to localize any potential TS gene(s).

The Search for Chromosomal Abnormalities in TS

While most TS patients have normal karyotypes, some incidental reports have described chromosomal abnormalities. Each of these reports has been examined in greater detail, since the site of a chromosomal rearrangement may provide a clue to the localization of a gene for TS.

Comings and colleagues44 reported a balanced reciprocal translocation in six relatives with TS. This report suggested that a gene for TS may be located near the 18q22.1 breakpoint seen in these patients. Subsequently, Donnai⁴⁵ reported a female patient with a mildly hypoplastic midface, tic-like movements, mild OCD, panic attacks, and visual hallucinations. This woman carried a deletion of the long arm of chromosome 18 at 18q22.1. Given the relationship between OCD and tics, this report provided additional support for the hypothesis that a gene for TS may be located in this region. Together, these two reports led to the tentative assignment of the TS gene to chromosome 18q22.1 by the Chromosome 18 Committee at Human Gene Mapping Conference IX (Paris, 1987). This location, however, remains unconfirmed. Another cytogenetic abnormality (a de novo deletion on the short arm of chromosome 9) was reported in a Latin-American male TS patient by Taylor and colleagues.⁴⁶ The patient was mildly dysmorphic with microcephaly, prominent supraorbital ridges, and slight midfacial hypoplasia. He also exhibited a number of characteristics of the 9p deletion syndrome in the oral cavity and the fingers. In addition, a recent study by Gericke et al⁴⁷ found a chromosomal fragility at 22q12-13 among 12 male subjects. This fragility was not observed in 10 normal control males. Unfortunately, linkage analyses using probes specific for these chromosomal regions have not confirmed the linkage of a gene for TS to any of these regions.⁴⁸

Candidate Gene Approach

Genes coding for proteins (eg, enzymes, receptors, or transporters) that are possibly involved in the etiology of a disease are referred to as candidate genes. If the candidate gene is the same as the disease gene, it will cosegregate with the disease in the families studied.

However, this approach to gene identification is limited by the current availability of cloned genes with known neurologic functions, and by the lack of convincing evidence concerning altered biologic pathways in TS. At this point in our understanding of of the basic biology of TS, any gene involved in central nervous system function becomes a candidate gene. The DNA markers for a number of candidate genes, such as the dopamine receptor family, dopamine b-hydroxylase, pro-dynorphin pro-opiomelanocortin tyrosine hydroxylase, gastrin-releasing peptide serotonin transporter (SLC6A4), and several classes of serotonin receptors have been tested to date. All of these loci have been excluded as the gene conferring susceptibility for TS.^48-54 Association studies provide an additional means of testing candidate genes, as well as other loci. In this approach, cosegregation of a specific allele of a locus with the disease is studied in patients and matched controls. The goal of these analyses is to determine whether the allele and the disease co-occur more frequently than can be expected by chance alone.

Association may be caused by the marker being located at or in the near vicinity of the functional mutation in the gene. Alternatively, it may occur because the marker is close to a gene that modifies the expression of the disease. When modifier genes are involved, the phenotype results from the interaction of alleles at two or more loci.

An alteration in the dopamine system is the leading hypothesis for an etiologic genetic defect in TS.⁵⁵ Several reports of possible associations between dopaminergic genes (the dopamine D₂ and D₃ receptor loci) and TS have been published.^56,57 These initial results, however, have not been replicated consistently in well-defined, large groups of TS patients.^49,58

The D5 receptor locus was excluded from linkage by Barr et al⁵⁴ in five large TS kindreds. An article by Grice et al⁵⁹ utilized another nonparametric analytic method, the transmission disequilibrium test,⁶⁰ to examine any potential linkage between TS and the D4 receptor locus (DRD4). The DRD4 locus is particularly interesting because it contains a polymorphism in the exon coding for its putative third cytoplasmic loop of the protein, with several major allelic variants. Each of these variants results in measurably different pharmacokinetic properties of the receptor. The DRD4*7R allele was transmitted to TS patients in this study more frequently than other alleles. Although the same data were examined using other analytic linkage and association methods, none of those results produced a significant finding. While the initial result is intriguing, similar analyses using independent samples from other laboratories did not replicate the findings (D.L. Pauls, unpublished data, 1997). Thus, the findings of dopaminergic gene associations with TS remain preliminary at best.

Systematic Search for Polymorphic Markers Linked to the Disease Locus

Since all published reports of genetic analyses suggest that the TS spectrum has a single major locus contributing significantly to the inheritance of TS (although a multigenic background is not excluded), a more comprehensive approach to finding a TS gene or genes is warranted. A systematic whole-genome linkage study of TS is under way in several laboratories that contribute independent data as a part of the whole study.^53,61 These studies generate DNA typing information using large multigenerational kindreds⁶² and the highly polymorphic markers that have been mapped in the Human Genome Project.

Pauls et al⁶¹ reported the results of linkage analyses of the first 180 markers typed in the TS linkage study. No significant evidence for linkage was obtained. At the present time, over 600 marker loci have been typed; a substantial proportion of the genome has been excluded from linkage with TS. A working estimate is that at least 75% of the autosomal genetic map has been excluded if it is assumed that CTs are part of the inherited spectrum of TS. An exact calculation of the proportion of the genome that has been excluded is not possible for several reasons, however. First, if TS is genetically heterogeneous,⁶³ exclusion in one family does not imply exclusion in another. (Pakstis and colleagues⁵³ pointed out that an important assumption of these analyses is that the major locus for TS is the same in different pedigrees under study.) Second, the exact length of the human autosomal map is not known. Third, exclusion zones of markers that are not precisely mapped may overlap with well-localized markers.

Finally, exclusions are dependent upon the genetic model specified in the linkage analyses. Since the "true" genetic parameter values are not known, and since these values may also differ across the families being studied (genetic heterogeneity), it is not possible to estimate precisely the extent of the current exclusion. Given the likelihood that TS is a heterogeneous disorder, additional strategies are being employed that do not rely upon the specification of a specific genetic model for the analyses.

Sibling-pair Analysis

Given the current lack of success in finding susceptibility genes for TS using large multigenerational families,^53,64 alternative strategies have been initiated in the search for susceptibility loci. As Pauls⁶⁵ has discussed, a possible shortcoming of existing linkage studies is the reliance on large multigenerational families. While distinct advantages exist to using large families (including increased statistical power and increased probability of genetic homogeneity), the use of large pedigrees also carries limitations. Several caveats must be kept in mind when considering the use of large multigenerational pedigrees.⁶⁶ First, it is less likely that the findings from large pedigrees will be generalizable to the more common form of the disease in the larger population. Second, it is not clear that large pedigrees guarantee homogeneity. Third, large multigenerational families are difficult to ascertain. Fourth, large pedigrees are less useful for additional types of studies (ie, sibling-pair studies, association studies, and segregation analysis studies).

A large sample of small families can provide distinct advantages over a small sample of large families. One method, the use of affected sibling-pairs, offers an advantage in that no prior assumptions regarding specific genetic mechanisms of a disease are required: It is essentially a model-free procedure. The analytic approach to sibling-pair studies relies on the comparison of the number of alleles at a given locus that are shared by two affected siblings across all families in the sample. If the number of affected siblings sharing an allele or alleles is significantly higher than that expected by chance, it suggests that a gene of etiologic importance for the trait in question is close to the marker examined.

An affected sibling-pair sample also allows for the examination of hypotheses concerning the transmission of possible subtypes of disorders and the application of a wider range of analytic methodologies. Therefore, investigators have begun to collect TS-affected sibling-pair families for an initial screen of the entire human genome. While the sibling-pair approach has been available for some time, its application is becoming increasingly important in the study of disorders where genetic heterogeneity is a possibility and where the mode of inheritance is complex.

It has recently been shown that even smaller samples of discordant sibling-pairs have a greater power than affected sibling-pair studies for detecting linkage for quantitative traits.^67,68 Unfortunately, no assessments are currently available that provide a suitable measurement of either TS or OCD as rigorous quantitative phenotypes.

Imprinting

Genomic imprinting refers to the phenomenon whereby altered expression of a genetic locus is dependent upon the gender of the parent transmitting the allele.69 One of the better-studied examples of imprinting in a human disorder is the Angelman's/Prader-Willi locus on chromosome 15.70 These two very different phenotypes result from gender-specific transmission of the identical mutation. If the causative deletion is transmitted on the maternally derived chromosome, Angelman's syndrome will result, whereas Prader-Willi syndrome stems from transmission of the identical deletion on the paternally derived chromosome. Three recent papers have examined the question of genomic imprinting in TS. While there is no molecular evidence (such as that which exists for Angelman's/Prader-Willi syndrome), the family data are intriguing. Furtado and Suchowersky⁷¹ reviewed the charts of 36 TS patients in whom maternal or paternal transmission of the disorder was clearly evident. Their results indicated no difference between the two groups in age of onset, motor tic and phonic tic symptom profiles, attention problems, obsessive-compulsive symptoms, and hyperactivity.

A somewhat different conclusion was reached by Lichter et al⁷² in 1995. These authors retrospectively examined data on 25 maternally transmitted and 25 paternally transmitted TS patients. Significant differences between the two groups were found: Maternal transmission was characterized by greater motor tic complexity and more frequent noninterfering rituals, while paternal transmission was characterized by increased vocal tic frequency, a longer onset interval between vocal and motor tics, and increased motor restlessness. The different findings in these two studies may be attributable to the greater depth of patient symptom information that was available to Lichter and colleagues.

A larger study was conducted by Eapen et al,⁷³ who examined 437 first-degree relatives of 57 TS probands by direct clinical interview. These researchers found no significant differences in phenotypic expression between 73 demonstrably matrilineal cases and 61 demonstrably patrilineal cases. The age of onset, however, was significantly lower in maternally transmitted TS. This provides further evidence of an imprinting effect on the putative TS gene(s). Such interesting findings may lead to a fruitful re-examination of previous genetic analyses of TS.

Outlook

The localization of a gene or genes involved in the expression of TS will be a major step forward in our understanding of the genetic/biologic factors that are important in this syndrome. The identification of a linked DNA marker will permit the design of much more incisive studies to illuminate the developmental, physiologic, and biochemical etiology of TS. These studies can include examination of the gene product itself, the regulation of its expression, its interactions with other systems, and ultimately its impact on the manifestation of the syndrome.

Additionally, controlling for known genetic factors will allow the study of potential nongenetic factors associated with the manifestation or amelioration of symptoms.^74,75 It should become possible to understand more fully the interrelationships among environmental and nongenetic factors that are important in the expression of the TS spectrum.

Once the location of a gene or genes has been verified, it will be possible to genotype unaffected children at risk to determine with a high probability which children carry a susceptibility gene. It will then be possible to focus on the interaction between those individuals' genotypes and environments. Linked genetic markers can serve as the basis for defining an appropriate control group for a genetic case-control design.⁷⁶ Closely linked genetic markers can accurately identify those children who are genetically identical with their affected siblings and/or parents for the relevant loci.

The ability to utilize genetic linkage to design and execute studies of nongenetic etiologic factors of a psychiatric illness would be a significant methodologic advancement that has not yet been available in the study of human behavior. Data from prospective studies of children at risk will make it possible to examine individuals with specific genotypes to determine which factors protect some from manifesting TS.⁷⁷ As the search for a linked marker progresses, it is critically important to begin collection of environmental data now, before genes are localized. After genes are localized, it will be ethically unacceptable to withhold the test for identification of carriers from individuals at risk who request testing, and knowledge of carrier status may change the caregiving environment. While this will prove advantageous for children at risk, it will severely limit the ability to understand the family and social interactions relevant to TS susceptibility.

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• Dr. Alsobrook is an associate research scientist at the Child Study Center, Yale University School of Medicine, New Haven, CT.

  Acknowledgment: This work was supported in part by a Young Investigator Award from the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD). Dr. Alsobrook is the NARSAD Maltz Investigator.

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