Download Mulle JG, Warren ST. Genomic tics in tourette syndrome. Biol Psychiatry. 2012 Mar 1;71(5):390-1. doi: 10.1016/j.biopsych.2011.12.017. No abstract available.

COMMENTARY
Genomic Tics in Tourette Syndrome
Jennifer G. Mulle and Stephen T. Warren
t is a striking observation that studies of copy number variation
(CNV) in neurodevelopmental phenotypes continue to report
an excess of rare variants in case populations. This astonishing
result has been observed and replicated in studies of intellectual
disability (1), autism (2), schizophrenia (3), and epilepsy (4). In a
study published this month in Biological Psychiatry, Tourette syndrome (TS) is now added to this growing list (5).
In their newly published study, Fernandez et al. (5) found a
2.45-fold excess of de novo CNV in cases compared with controls. They also found that these CNVs are larger and affect more
genes than de novo events present in controls. Although these
results are not statistically significant, owing to the small sample
size under study, this trend is similar to what has been seen for
other neurodevelopmental phenotypes, including autism. Additionally, TS case CNVs are enriched for autism candidate genes,
such as contactin-associated protein-like 2 (CNTNAP2), fragile
histidine triad protein (FHIT), and astrotactin 2 (ASTN2). This
result does reach statistical significance, suggesting that there is
a shared pathway between TS and autism. The shared-pathway
hypothesis is supported by a prior report of a neuroligin 4
(NLGN4) deletion discovered in an autistic proband. In this pedigree, a brother of the autistic proband who shares the NLGN4
deletion has TS (6). One interpretation of these data is that
inherited susceptibility alleles give rise to a core neurobiological
insult that could result in any of a range of phenotypes. Current
evidence suggests that this range includes both TS and autism,
with environmental influences or modifier genes mediating the
specific phenotypic manifestation. These intriguing hypotheses
will require additional investigation in larger cohorts of TS patients.
The authors chose to explore the qualitative nature of genes
affected by rare CNV in their TS cases, using well-known methods
to identify biological pathways or processes that might be commonly affected in their TS cases. They find evidence for involvement of the histamine receptor-signaling pathway. This dovetails with prior work of these authors, in which they investigated
a Mendelian form of TS. In a pedigree with nine affected individuals, in which TS is segregating in a dominant fashion, linkage
analysis, and subsequent sequencing of all genes in the linkage
interval identified a rare stop codon mutation in the gene for
L-histidine decarboxylase, the rate-limiting enzyme in histamine
production (7). The authors showed that this mutation led to a
decrease in both enzyme activity and histamine concentration,
suggesting that a decrease in histamine transmission may underlie some forms of TS.
In a very recent case report of an adult male with TS and
narcolepsy, a pharmacologic intervention was tailored based on
the results of the pedigree analysis discussed above. The patient
had been treated with various agents, and although some were
successful in treating his narcolepsy, they simultaneously in-
I
From the Department of Epidemiology, Rollins School of Public Health
(JGM) , Emory University; and Department of Human Genetics, Emory
University, School of Medicine (STW), Atlanta, Georgia.
Address correspondence to Jennifer G. Mulle, Ph.D., Department of Epidemiology, Rollins School of Public Health, CNR 4053, Atlanta, Georgia
30322; E-mail: [email protected].
Received and accepted Dec 21, 2011.
0006-3223/$36.00
doi:10.1016/j.biopsych.2011.12.017
creased his tics. The treating clinicians, inspired by the hypothesis of diminished histaminergic activity in TS, chose to treat the
narcolepsy with a histamine agonist specific to the H3 receptor
(BF2.649 or tiprolisant or pitolisant) to boost histamine signaling
(8). The patient’s narcolepsy improved, and his tics did not
worsen (although they did not improve); this was sustained over
9 months. Taken together, these exciting results suggest histamine metabolism or signaling as a potential target for treatment
of some patients with TS.
Fernandez et al. (5) observed a statistically significant approximately 6-fold excess of deletions at the FHIT locus in TS cases.
However, these deletions had highly similar endpoints despite no
flanking segmental duplications. One homozygous deletion was
also seen. In the face of this evidence, the authors concluded this
deletion was not recurrent and was instead likely inherited from a
common ancestor shared by the individuals carrying the FHIT deletion alleles. This in turn implied the existence of residual population
stratification in their sample, despite efforts to remove such influences with widely accepted methods. The authors took a conservative approach and excluded the FHIT locus.
An alternative explanation may exist. The FHIT gene includes the
common fragile site FRA3B. Replication stress has been shown to
induce submicroscopic deletions at this locus (9). It is therefore
possible that deletions at this locus are in fact recurrent, mediated
by replication stress and nonhomologous end joining. This would
be consistent with some of the breakpoints not being precisely the
same and not to require nearby segmental duplications to mediate
recurrence. Although the exclusion of this locus is appropriate until
population subdivision can be ruled out, the deletion of the FHIT
gene may yet represent one pathway for development of TS and
deserves further attention.
The observation of excess de novo CNVs is becoming such a
common feature of many neuropsychiatric disorders that one
may wonder whether these events are a fundamental feature of
these disorders in general or really do point out specific genomic
regions in which dosage can impart a substantial predisposing
risk. It is therefore reassuring that not all neuropsychiatric disorders exhibit enrichment of de novo CNVs, such as a recent study
comparing individuals with intellectual disability (ID), autism, or
dyslexia, all performed on the same platform with the same
analysis (1). Although excess de novo CNVs in ID and autism
replicated many earlier studies, dyslexia showed a burden of de
novo events no different from controls. The observations by
Fernandez et al. (5) likely provide significant insight into the
basis of TS, a disorder long known to have a genetic component
but until these recent data resisted revealing the genomic lesions responsible.
Dr. Warren is chair of the scientific advisory board of Seaside Therapeutics, Inc. Dr. Mulle reports no biomedical financial interests or
potential conflicts of interest.
1. Girirajan S, Brkanac Z, Coe BP, Baker C, Vives L, Vu TH, et al. (2011): Relative
burden of large CNVs on a range of neurodevelopmental phenotypes.
PLoS Genet 7:e1002334.
2. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-DeLuca D, et al. (2011): Multiple recurrent de novo CNVs, including duplica-
BIOL PSYCHIATRY 2012;71:390 –391
© 2012 Society of Biological Psychiatry
Commentary
tions of the 7q11.23 Williams syndrome region, are strongly associated
with autism. Neuron 70:863– 885.
3. International Schizophrenia Consortium (2008): Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241.
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5. Fernandez TV, Sanders SJ, Yurkiewicz IR, Ercan-Sencicek AG, Kim Y-S,
Fishman DO, et al. (2012): Rare copy number variants in Tourette syndrome disrupt genes in histaminergic pathways and overlap with autism.
Biol Psychiatry 71:392– 402.
BIOL PSYCHIATRY 2012;71:390 –391 391
6. Lawson-Yuen A, Saldivar JS, Sommer S, Picker J (2008): Familial deletion
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CE, et al. (2010): L-histidine decarboxylase and Tourette’s syndrome.
N Engl J Med 362:1901–1908.
8. Hartmann A, Worbe Y, Arnulf I (2011): Increasing histamine neurotransmission in Gilles de la Tourette syndrome [published online ahead of
print July 22]. J Neurol. doi:10.1007/s00415-011-6171-1.
9. Durkin SG, Ragland RL, Arlt MF, Mulle JG, Warren ST, Glover TW (2008):
Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proc
Natl Acad Sci USA 105:246 –251.
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