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European Journal of Neurology 2014, 21: 637–642 doi:10.1111/ene.12366

Huntingtin gene CAG repeat numbers in Chinese patients with

Huntington’s disease and controls
H. Jianga,b,*, Y. M. Sunc,*, Y. Haod, Y. P. Yane, K. Chenf, S. H. Xing, Y. P. Tangh, X. H. Lig,
T. June, Y. Y. Chend, Z. J. Liuc, C. R. Wanga, H. Lih, Z. Peig, H. F. Shangf, B. R. Zhange,
W. H. Gud, Z. Y. Wuc, B. S. Tanga and J.-M. Burgundera,f,g,i for The Chinese HD Network
a
Department of Neurology, Xiangya Hospital, Central South University, Changsha; bKey Laboratory of Hunan Province in Neuro-
degenerative Disorders, State Key Laboratory of Medical Genetics of China, Central South University, Changsha; cDepartment of Neurol-
ogy, Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai; dDepartment of Neurology,
China Japan Friendship Hospital, Beijing; eDepartment of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang
University, Hangzhou; fDepartment of Neurology, West China Hospital, Sichuan University, Chengdu; gFirst Affiliated Hospital of Sun
Yat-Sen University, Guangzhou; hDepartment of Medical Genetics, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, China; and iSwiss Huntington’s Disease Centre, Department of Neurology, University of Bern, NeuroBu Clinics,
Bern, Switzerland

Keywords:
CAG repeats, China,
huntingtin gene,
Huntington’s disease,
normative data
Received 10 August 2013
Accepted 17 December 2013
Background and purpose: Huntington’s disease is due to a CAG triplet repeat elon-
gation in the huntingtin gene. Boundaries in CAG numbers have been found
between healthy people with and without risk to pass the disorder to the next gener-
ation, and between people without, with a mild, or with a fully penetrant pheno-
type. These data have been generated in western populations and it is not clear
whether they are also valid amongst Chinese.
Methods: In order to establish normative data in the huntingtin gene for Chinese
people, 966 chromosomes from normal controls were tested. Further, the range of
CAG repeats was examined in a cohort from six centres and a total of 368 patients
with the disease were included.
Results: The CAG triplet repeat range in normal controls was between 9 and 35
(mean 18.9, SD 2.57). Triplets in the range between 26 and 35 were found in 2.5%. In
the patient cohort, triplet repeats in the shorter allele were between 8 and 37 (mean
17.7, SD 1.6). In the longer allele, a range between 36 and 120 was found. There was
a negative correlation ( 0.65, r = 0.42) between age at onset and the number of trip-
let repeats in the larger allele. The mean age at onset was 38 years, with a range
between 2 and 70 years. In 23 patients (6%) a childhood or juvenile onset was noted.
Conclusion: These data show comparable ranges of huntingtin gene CAG triplet
repeats in normal people and in patients with Huntington’s disease as in western
populations.

symptoms leading to progressive impairment [1].

Introduction
Huntington’s disease (HD) is a progressive neuropsy-
chiatric disorder with motor, cognitive and behaviour
Correspondence: Z. Y. Wu, Institute of Neurology, Fudan
University, Department of Neurology, Huashan Hospital, Shanghai
Medical College, Fudan University, 12 Wulumuqi Zhong Road,
Shanghai 200040, China (tel./fax: +86 21 62483421; e-mail:
zhiyingwucn@yahoo.com.cn).
J.-M. Burgunder, Department of Neurology, University of Bern,
NeuroBu Clinics, Steinerstrasse 45 CH-3006 Bern, Switzerland
(tel.: +41 31 352 20 70; fax: +41 31 351 80 70; e-mail: jean-marc.
burgunder@dkf.unibe.ch).
*Jiang Hong and Sun Yimin have contributed equally to the
work.Wu Zhi-Ying and Jean-Marc Burgunder for the Chinese Hun-
tington’s Disease Network.
Service-based prevalence is 5.7 per 100 000 (CI 4.42–
7.35) in Europe, North America and Australia [2],
with a higher prevalence of 12.4 in Great Britain [3].
In a new UK study the estimated prevalence of adult
HD patients was 12.3 in 2010, rising from 5.4 over
20 years, with large regional differences [4]. Reported
HD prevalence in Asia is much lower with 0.11–0.72
per 100 000 [5], and point prevalence in Hong Kong
was 0.25 per 100 000 [6]. In a recent review of the
Chinese literature from mainland China databases on
HD covering the years 1980 2011 [7], 92 studies
involving 279 patients were found with enough data
to perform a survey. This survey demonstrates that

© 2014 The Author(s)

European Journal of Neurology © 2014 EFNS 637

638 J. Hong et al.
indeed HD is found in several regions of the country
and suggests that it may have been under-reported.
Huntington’s disease is an autosomal disorder due
to a variable increase in the number of triplet repeats
at the 5′ transcribed region of the huntingtin gene [8].
In normal people the two alleles contain up to 26
CAG repeats. Triplet numbers between 26 and 35 are
not associated with disease manifestation but with
increased risk for children to have higher repeat num-
bers due to a dynamic mutation pattern [9]. Persons
with 36–39 CAG repeats on the larger allele are
affected with lower penetrance; those with 40 or more
repeats have a more than 90% probability of being
affected by the age of 65 [10]. These numbers have
emerged during the analysis of several, partly large,
series in the West, but controversy remains with
reports of affected people within the intermediate
range [11]. A cohort including Chinese controls and
HD patients has been reported in Taiwan [12]. Nor-
mal chromosomes had 10–29 CAG repeats with an
asymmetrical distribution and affected people had an
expansion between 38 and 109. A recent haplotype
analysis has suggested that specific variants associated
with an increased risk of expanded triplet repeats are
absent in Asian populations, which would explain the
lower prevalence [13]; however, this study comprised a
low number of Chinese participants.
Therefore, there is a need to increase our knowledge
on the exact number of huntingtin gene triplet repeats
in the general population in China. Specifically, the
boundaries of triplet repeat numbers between normal,
at risk for transmitting the disease to the next genera-
tion, at risk of developing the disease with low or high
penetrance have not been well defined in the Chinese
population. It may be wrong to assume that they are
the same as in the West, where these boundaries have
been established after a number of investigations.
Considering the fact of increasing awareness of the
disorder in China, the availability of such data is of
utmost importance in the clinical context, specifically
for practical diagnostic processes and for genetic
counselling. Differences in this aspect of the pheno-
type between Chinese and other populations so far
studied would also help to shed light on epigenetic,
genetic and environmental modifying factors. A sur-
vey was therefore undertaken of the range of CAG
repeat numbers associated with HD diagnosis in sev-
eral centres in China and triplet number repeats in
healthy Han Chinese were examined.
Method
The number of triplet repeats in the huntingtin gene
was examined in 483 healthy Chinese of Han origin
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without a family history for HD. Primers, forward 5′-
CAGAGCCCCATTCATTGCC-3′ and reverse 5′-
TGAGGAAGCTGAGGAGGC-3′, were used to
amplify the region containing unstable CAG repeats
in huntingtin gene exon 1. The PCR system contained
2.5 ll of 50 lg/ml genomic DNA, 4 ll of 2.5 lM
dNTP, 0.5 ll of 10 lM primers, 12.5 ll of 2 9 GC
buffer (Takara, Japan) and 0.25 ll of LA Taq DNA
polymerase (Takara, Japan), supplemented with water
to 25 ll. PCR cycling conditions were initial denatur-
ation at 95°C for 3 min, followed by 35 cycles of
94°C for 30 s, 62°C for 45 s and 72°C for 60 s with a
final extension at 72°C for 7 min. Three microlitres of
amplified DNA products were analysed by 6% poly-
acrylamide gel electrophoresis and purified PCR prod-
ucts were sequenced at Beijing Genomics Institute.
Data from the case cohorts followed up at the
Departments of Neurology or Genetics participating in
the recently launched Chinese Huntington’s Disease
Network were collected. Included in the HD group were
persons with a positive HD genetic testing result and
typical symptoms. The most commonly used method
for genetic testing was PCR amplification of the hun-
tingtin exon 1, followed by polyacrylamide gel electro-
phoresis and sequencing with CAG repeats count.
Symptomatic gene carriers were classified as affected
when they had typical features of HD, including
motor, cognitive and psychiatric involvement. Infor-
mation was collected on reported age at onset of HD
symptoms and number of repeats at the shorter and
at the longer allele. Collection of patient data at the
different centres was done according to the local rules,
and the ethical review boards at the participating cen-
tres have approved the study.
Data analysis was performed by plotting the fre-
quencies of individual length in controls and of the
shorter allele in affected or at risk gene carriers. In
gene carriers, the relationship between the number of
CAG repeats on the larger and the age at onset was
examined. The Pearson test was used to calculate the
correlation between age at onset and number of CAG
repeats in the larger allele. Comparison of CAG trip-
let numbers in the smaller allele in affected with the
the number found in normal controls was performed
using a two-tailed t-test.
Results
The range of CAG repeat numbers in normal controls
including 966 chromosomes was between 9 and 35; the
mean was 18.9 (SD 2.57) (Fig. 1). In 24 chromosomes
(2.6%) triplets in the range between 26 and 35 were
found. The skewness of the distribution curve was 2.56.
Amongst the six participating centres, 368 patients with
© 2014 The Author(s)
European Journal of Neurology © 2014 EFNS
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CAG numbers in China 639

Figure 1 Frequency distribution of the

number of triplet repeats in the hunting-
tin gene in a normal Chinese population
(n = 966 chromosomes).

HD diagnosed by experienced neurologists were found;
the range of triplet repeats in the shorter allele was 8–
37 (mean 17.7, SD 1.6) (Fig. 2). No difference was
found with the numbers counted in the normal controls
(P = 0.12). In the longer allele, a range between 36 and
120 CAG was found. One HD patient with age at onset
of 42 years had 36 CAG in the smaller allele (43 in the
larger one), and one with an age at onset of 14 had 37
CAG (56 in the larger one). Two HD patients had
CAG repeat numbers associated with intermediate
alleles in their lower alleles. The first had an onset at
42 years with 26/42 repeats, the second an age at onset
of 31 years with 32/45 repeats. In nine cases (2.5%) the
larger allele was in the range between 36 and 39.
There was a negative correlation ( 0.65, r = 0.42)
between age at onset and the number of triplet repeats
in the larger allele (Fig. 3). The range at onset varied
from 2 to 70 years and in 23 patients (6%) a child-
hood or juvenile onset was noted (2–20). The mean
age at onset was 38 years (Fig. 4).
In this cohort 34 at risk persons were also found,
asymptomatic at the last contact, which occurred
when they were 18–45 years old. The range of triplet
numbers in these cases was between 39 and 49.
Discussion
The number of triplet repeats in normal Chinese was
within similar limits found in other countries, with a
mean between 16 in African Blacks to 18 amongst
Europeans [14]. In Mexicans, the reported mean of
19.04 was significant higher [15], and in a large Vene-

Figure 2 Frequency distribution of the

number of triplet repeats in the hunting-
tin gene in affected people with HD (368
persons from six centres) in the allele
with lower CAG repeat numbers (which
are also within the normal range shown
in Fig. 1) and in the allele with higher
CAG repeat numbers.

© 2014 The Author(s)

European Journal of Neurology © 2014 EFNS

640 J. Hong et al.
zuelan cohort the range was 9 34 [16]. In a control
group of Japanese, the range was 7–29 [17]. These
data also confirm smaller sets of Chinese subgroups
included in previous surveys, e.g. 10 Chinese with 16–
20 CAG repeats in a larger series [18], as well as the
12–27 in Hong Kong [19] and Taiwan [20].
In a comparative analysis of several populations,
increasing skewness of distribution towards higher
positive values was found; they were lowest in Afri-
cans and highest in Japanese, the Indian value being
in between [21], and this has been suggested to be
related to the mutation rate in a given population.
The value in our cohort is lower than those in other
populations and may be related to the presumed lower
prevalence of HD in China.
The lower limit of 36 CAG repeats in our popula-
tion with manifest disease is comparable to what has
been observed so far in other populations, e.g. in New
England [22] or in the Venezuelan cohort [16]. The
lower limits reported in affected people of other ori-
14681331, 2014, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.12366 by Pontificia Universidad Catolic, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Figure 3 Relationship of reported age at
onset with the number of CAG triplet
repeats in the huntingtin gene.
gins include 42 in Dutch people [23], 41 in Russian
[24], 39 in Germans and Danes [25, 26] and 37 for
Italians [27]. In a cohort of 95 Japanese HD patients,
the range was between 37 and 95 [17], and in a recent
publication about Korean HD patients the range was
40 58 [28]. Our data are also compatible with
Chinese literature case reports [7] and with a smaller
series in southern China [19]. In a previous study
amongst 35 HD patients from 11 families in Taiwan
the range was 40 58 [20].
Intermediate alleles with CAG numbers between 27
and 35 are linked with a higher risk of expansion in
the next generation but their potential association
with the disease phenotype had been debated. A
recent analysis of 50 patients in a larger cohort who
had intermediate alleles provided evidence of subtle
behavioural changes including suicidal thoughts and
apathy [29]. The relative number of alleles in the inter-
mediate range found in our normal cohort (2.6%) is
lower than the 3.2% [22] to 6% [9,30] demonstrated
Figure 4 Age at onset of symptoms in
patients with HD.
© 2014 The Author(s)
European Journal of Neurology © 2014 EFNS

in previous large series; this may also be related to the
presumed lower prevalence.
The negative correlation between numbers of triplet
repeats and age at onset has been found in all popu-
lation studies and is now confirmed amongst Chinese
HD patients. In our population, however, only 46.6%
of the variation in age at onset is explained by the
number of triplet repeats, which is lower than in
other studies, with ranges between 50.4% [31] and
72% in a large cohort [16] and even values up to
79% in a smaller one [32]. The reasons for this dis-
crepancy are not clear but could be related to genetic
or environmental factors which would modify age at
onset.
The distribution of the ages at onset in our cohort
is similar to previous descriptions in Caucasians. One
of the youngest cases, with onset at 3.5 years, has
been described in more detail earlier [33]. Likewise,
previous papers have examined a group of patients
with higher triplet repeat numbers [34], intergenera-
tional triplet expansion [35] and contraction [36].
Potential variations in CAG numbers between labo-
ratories may be a limitation of such a multicentre sur-
vey, but this is a common finding, as demonstrated in
a systematic comparative analysis in the European
Huntington’s Disease Network [37], and the similarity
of our data confirms the general validity of our inter-
pretation. The low number of intermediate and low
penetrance CAG range does not allow firm conclu-
sions about the phenotype in this group. Use of
historical data about age at onset and appearance of
motor symptoms as disease onset may not be truly
representative of phenoconversion. Furthermore,
whether the phenotype is the same in Chinese com-
pared with the West is not known. There is therefore
a need to use a more comprehensive assessment of dif-
ferent symptom modalities including cognitive and
behaviour changes, avoiding preconception as to the
type of symptoms felt to demonstrate disease onset.
The Chinese Huntington’s Disease Network has been
founded in order to further examine aspects of the
phenotype amongst Chinese, and this should also help
in addressing the above limitations. Furthermore
aspects of the phenotype might differ between ethnic
groups and this could provide further ways for com-
parative studies about genetic and environmental
modifiers.
Acknowledgements
Work of the Chinese Huntington’s Disease Network
is supported by CHDI. This study was supported by
the National Basic Research Program (973 Program)
(nos. 2012CB944601, 2012CB517902 and 2011CB510
© 2014 The Author(s)
European Journal of Neurology © 2014 EFNS
14681331, 2014, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.12366 by Pontificia Universidad Catolic, Wiley Online Library on [06/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CAG numbers in China 641
002 to Hong Jiang), New Century Excellent Talents in
University from the Ministry of Education of China
(no. NCET-10-0836 to Hong Jiang), the National Nat-
ural Science Foundation of China (no. 81271260 to
Hong Jiang; No. 81371417 to Li He: National Natural
Science Foundation of China), Undergraduate Innova-
tion Project of Hunan Province (no. HN2013028 to
Hong Jiang), Undergraduate Innovation Project of
Central South University (no. CY12400 to Hong Jiang)
and the China Central Universities Fundamental
Research Funds to Yaping Tang. We thank the patients
and their families for their participation.
Disclosure of conflicts of interest
JIANG Hong: grants from the National Basic
Research Program (973 Program) (nos. 2012CB944601,
2012CB517902 and 2011CB510002), New Century
Excellent Talents in University from the Ministry of
Education of China (no. NCET-10-0836), the National
Natural Science Foundation of China (no. 81271260),
Undergraduate Innovation Project of Hunan Province
(no. HN2013028) and Undergraduate Innovation Pro-
ject of Central South University (no. CY12400). Jean-
Marc Burgunder: Co-Chair of the European Hunting-
ton’s Disease Network, with support by CHDI. Tang
Yanping: grant from the China Central Universities
Fundamental Research Funds.
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European Journal of Neurology © 2014 EFNS