• continued pregnancy;
  • exclusion test;
  • exclusion-definitive test;
  • grey test result;
  • Huntington's disease;
  • intermediate allele;
  • non-disclosure;
  • PD;
  • prenatal diagnosis;
  • reproductive decision making;
  • uptake


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.

Huntington's disease (HD) is an incurable, autosomal dominant inherited, neurodegenerative disorder. The disease is characterized by progressive chorea, cognitive impairment and psychiatric disturbances [1]. Onset of symptoms is usually between the ages of 35 and 44, and life expectancy at diagnosis is around 20 years. The HD gene was localized on chromosome 4 in 1983, enabling predictive linkage testing within families [2]. A decade later the HD causing genetic defect, an expanded trinucleotide (CAG) repeat in the HTT gene, was discovered [3], creating the possibility of performing individual pre-symptomatic testing (PT) in persons at risk. A CAG repeat size of up to 26 trinucleotides is considered to be normal. Intermediate alleles range from 27 to 35 repeats and are generally not associated with HD symptoms, but the CAG repeat can increase if the allele is transmitted to offspring. Alleles with 36–39 CAG repeats are associated with a reduced penetrance and alleles with a repeat size ≥40 are invariably associated with HD.

Preventing transmission of HD to offspring can be facilitated by prenatal testing of foetal DNA obtained through chorionic villus sampling or amniocentesis. The most frequently applied method is direct testing of the repeat size with a view of terminating the pregnancy if the foetus shows a CAG repeat size associated with HD (>35 repeats). If the at-risk parent prefers not to have his/her HD expansion status defined, exclusion testing can be performed by linkage analysis. The presence of one of the chromosome 4 haplotypes of the affected grandparent in the foetus is associated with a 50% risk of developing HD, equal to the at-risk parent [4]. If the foetus carries this so-called ‘50% risk haplotype’ the pregnancy is expected to be terminated. If, on the other hand, a couple objects to terminating a 50% risk pregnancy, an exclusion-definitive test may be used to determine the actual HD status of the foetus and at-risk parent [5]. Pre-implantation genetic diagnosis (PGD) may be an alternative for couples who are reluctant to terminate the pregnancy (TOP) for late-onset disorders such as HD or a 50% HD risk. By selecting in vitro fertilization (IVF) embryos without the CAG repeat expansion or the 50% risk haplotype (exclusion PGD), transmission of HD to offspring can be avoided [6-8].

This study aims to evaluate the number of prenatal tests, test results, and pregnancy outcomes in relation to repeat size of the at-risk parent in the Netherlands between 1998 and 2008 and compare these data with the preceding decade [5].

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

DNA analysis for HD in the Netherlands is centrally performed in the Laboratory for Diagnostic Genome Analysis in Leiden (LDGA). The results of all prenatal tests from 1998 to 2008 were retrospectively collected from the LDGA and, if applicable, the date of PT and CAG repeat size of the at-risk parent. Eight Dutch university departments of clinical genetics offer genetic counselling around pre- and postnatal testing for HD. Additional clinical information was collected in these centres in cooperation with the clinical geneticists involved. These data included information on gender and age of at-risk parents, reproductive history, and prenatal tests during the study period, including test results and pregnancy outcomes. All results were compared with those obtained in the Netherlands from 1987 to 1997 [5].

To estimate the uptake of couples applying for prenatal diagnosis (PND), our study population was compared with the number of HD carriers of reproductive age (arbitrarily set at females ≤40 years and males ≤50 years) undergoing PT in an 11-year period starting in October 1996.


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

A total of 126 at-risk couples opted for PND in the period 1998–2008. More than half of the at-risk parents (52%) were female (Table 1). The majority, 71% (89/126) of at-risk parents, had undergone PT for HD before their first prenatal test. Four individuals had PT at the same time as their first PND with the intention of having their carrier status defined independently of the PND result. For two of these couples, the first PND (and PT) had taken place prior to the study period. Significantly more females than males had performed a PT prior to or simultaneous to their first PND (83% of females vs 63% of males, p = 0.01). Thirty-three at-risk partners (26%), preponderantly males (M/F ratio 22/11), preferred not to know their HD expansion carrier status. None of the at-risk individuals had been diagnosed as clinically affected.

Table 1. Characteristics and reproductive history of couples undergoing prenatal diagnosis in the period 1998–2008

n = 126

n (%)

  1. PND, prenatal diagnosis; PT, pre-symptomatic test.

  2. a

    Including couples (n = 13) who had their first PND before 1998.

Gender at-risk partner/carrier CAG expansion
Male60 (48%) 
Female66 (52%) 
At-risk parent undergoing PT prior to/or at same time as first PND
Male38 (63%) 
Female55 (83%) 
At-risk parents not wishing to know their HD status: male/female22/11 
 mean (n) 
Age men at PT (if prior to first PND)30.3 (36)4.9
Age women at PT (if prior to first PND)26.3 (53)5.1
Male age at first PNDa33.0 (120)9.8
Female age at first PNDa30.0 (126)4.5
 n (couples) 
Untested children prior to first PND25 (19)
Pregnancies with PND prior to study period21 (13)

Fifteen percentage of couples (n = 19) had had one or more untested children before their first PND. In most cases, the HD diagnosis of a family member was not known before the pregnancy. Thirteen couples had a total of 21 prenatal tests prior to the study period.

In the study period, PND was performed in two pregnancies achieved by PGD to confirm the PGD result. The prior risk of showing HD after PGD is <1% [9]; therefore, these PND tests were excluded from the analysis.

Prenatal test results and pregnancy outcomes

A total of 216 prenatal tests were performed in 214 pregnancies in 126 couples (including 2 dichorionic twin pregnancies, Table 2). Direct tests were performed in 86% of PND (n = 185). In the remaining 14%, exclusion testing was performed (n = 31). For 168 direct tests (91%) the prior HD risk was 50%, 17 (9%) had a 25% prior risk for the foetus. Four at-risk parents whose carrier statuses were defined (after exclusion-definitive or direct PND testing for 25% HD) subsequently used direct PND. PND in 91 foetuses showed a CAG expansion ≥36 or a 50% risk allele (after exclusion testing). The majority of these pregnancies (82%, 75/91) were terminated, two ended in spontaneous abortion, one was terminated for congenital anomalies, and one was lost to follow-up. In all, 13% (12/91) of the foetuses with a CAG expansion or 50% risk allele were carried to term. These continued pregnancies will be described in more detail later. PND had ruled out or excluded the transmission of HD in 89% of the live born children (112/126). Two pregnancies at 50% prior risk were continued without obtaining the PND result. A total of 125 pregnancies (including one twin pregnancy) resulted in the birth of one or more liveborn children in 100 couples.

Table 2. Prenatal tests and pregnancy outcomes (1998–2008)Thumbnail image of

The intermediate alleles in eight foetuses (Table 2) were identical to the at-risk parents' shortest CAG repeat in four cases, whereas in two cases the intermediate alleles originated from the healthy spouse. On one occasion the intermediate allele was identical to the at-risk parent's longest allele consisting of 28 CAG repeats (simultaneously tested). The origin of one intermediate allele (27 repeats) remains unknown, because the parents were not tested.

Disclosure of HD carrier status of at-risk parents

An overview of all individuals with their carrier status as well as the number of prenatal tests is given in Table 3. In the group of 91 persons with a known HD status at the time of their first PND there were 77 carriers of a full penetrance allele (85%), 10 (11%) had a reduced penetrance allele and 4 (4%) had an intermediate allele. In the latter group two males had received this ‘grey’ PT result unexpectedly [10]. They were only prepared to receive a ‘positive’ or ‘negative’ result', and decided to undergo PND to avoid any chance of having an HD-affected child. A third male belonged to a family with one documented expansion of an intermediate allele into the full penetrance range after paternal transmission, which may be associated with an increased expansion risk for other family members. No information was available on the female intermediate allele carrier opting for PND. Two others had PT performed simultaneously with their PND, both showing intermediate alleles. The HD status of 27% (9/33) of at-risk individuals who initially did not want to know their status was defined as the result of one or more exclusion-definitive or direct PND tests (six were confirmed by PT). Five at-risk individuals directly or indirectly proved to carry a repeat expansion associated with HD, while four at-risk individuals proved to be free of HD. One of these couples had previously terminated two pregnancies because of a 50% HD risk (retrospectively unaffected) (Table 3).

Table 3. Disclosure of HD status of all at-risk parents undergoing prenatal testing (1998–2008)
 At-risk individuals


Gender at-risk parent


Moment of PTPND tests


Prior to PND

n (%)

Simultaneous to or after PNDa

n (%)

  1. F, female; HD, Huntington's disease; M, male; PT, pre-symptomatic test; PND, prenatal diagnosis; TOP, termination of pregnancy; n.a., not applicable.

  2. a

    Including indirect PT through direct PND, exclusion-definitive test, or simultaneous PT of at-risk partner.

  3. b

    Two at-risk parents showed no HD expansion after exclusion-definitive test. One had two TOPs for 50% risk alleles (retrospectively unaffected).

  4. c

    CAG repeat sizes were 29, 30, and 33 repeats (at-risk male) and 31 repeats (at-risk female), respectively.

  5. d

    One exclusion-definitive test and one PT after PND had shown HD in foetus.

  6. e

    One dichorial twin represented two PND tests.

  7. f

    Two parents performed PT after PND had shown HD in the foetus, one parent opted for PT after having an unaffected child (PND normal).

  8. g

    One dichorial twin represented two PND tests.

  9. h

    Full HD expansion detected in PND, no confirmative PT in at-risk parent.

  10. i

    One couple opted for exclusion-definitive test confirming no HD carrier. Two direct PND tests in another couple had shown four different normal CAG repeats, indirectly suggesting the presence of two normal alleles in the at-risk parent.

CAG expansion (longest allele) if tested: ≤2621/1 2b (100%)4
27–3563/34c (67%)2 (33%)7
36–39127/510 (83%)2d (17%)20e
≥408031/4977 (96%)3f (4%)145g
HD status disclosed indirectly
HD carrier10/1 1h2
No HD22/0 2i4
50% HD risk (HD-status undisclosed)2316/7 n.a.34

Continued pregnancies with CAG expansion ≥36% or 50% risk haplotype

Information on the 12 continued pregnancies of foetuses showing a CAG repeat expansion associated with HD or a 50% risk haplotype is presented in Table 4. The age of the at-risk parents did not significantly differ from the age at PND of other couples (data not shown). The proportion of continued pregnancies (Table 2) varied between the different subgroups: 7 out of 71 (9.9%) full penetrance alleles, 3 out of 8 (37.5%) reduced penetrance alleles and 2 out of 12 (50%) risk alleles. No pregnancies were terminated for an intermediate allele. Two out of four pregnancies with a prior risk of 25% and CAG repeats ≥36 indicating ‘double bad news’ were continued. In the majority (8/10) of continued pregnancies with CAG expansions, the at-risk parent was female. Six couples showed a reproductive history with TOP (n = 3), miscarriages (n = 3) or threatened abortion (n = 1). Two couples had untested children.

Table 4. Continued high-risk pregnancies
Test result Gender at-risk parentReproductive historyCAG repeats foetusSpecific information on continued pregnancy
  1. F, female; HD, Huntington's disease; M, male; PGD, pre-implantation genetic diagnosis; PND, prenatal diagnosis; PT, pre-symptomatic testing; TOP, termination of pregnancy.

High-risk allele after exclusion test (n = 2)1MMissed abortion after first exclusion test, discovered at the moment of preparation for TOPHospital refused to offer future exclusion PND, which was notified simultaneously with PND result
2MFirst pregnancyNo additional information
Reduced penetrance allele (n = 3)3FTOP for neural tube defect (37 CAG repeats)37Same repeat size (37) as previous pregnancy and similar to at-risk parent
4FTOP without PND, unplanned pregnancy?39CAG repeat length identical to at-risk parent
5M≥1 untested child(ren) with previous partner. After continued pregnancy again PND with normal result38At-risk parent (39 CAG repeats) was simultaneously tested with PND
Fully penetrant allele (n = 7)6MTwo pregnancy terminations for HD, one unaffected child and two miscarriages (one after PGD)44Two previous terminations showed 47 and 52 CAG repeats
7F≥1 untested children (one with previous partner)43At-risk parent had not performed PT prior to PND. Very disappointed after double bad news, not able to terminate
8FTwo miscarriages40Couple had agreed to terminate if >44 repeats(> at-risk parent)
9FFirst pregnancy, in a subsequent pregnancy couple requested PND without intention to terminate if affected. This request was refused40At-risk parent showed 42 repeats. Pregnancy occurred during PGD preparation. Couple opted for PND, but a missed abortion was seen on two successive ultrasounds. A third ultrasound showed an intact pregnancy after all: PND was performed resulting in HD. Couple was not able to terminate after the disappointment of an abortion had been replaced by the relief of having an intact pregnancy
10FFirst pregnancy41Couple had agreed to terminate if 40 or more, foetus showed a repeat size of 41 only
11FFirst pregnancy, in a subsequent pregnancy couple requested PND without the intention to terminate if affected, which was refused44No additional information
12FNo information available47No additional information

Annual PND tests for HD performed in the Netherlands in the period 1988–2008

Figure 1a shows the yearly number of PND tests from 1988 to 2008. After the first application in 1989 there was an increase in numbers of PND for several years. Since 1996, the number of tests has remained quite stable with approximately 20 PND tests per year. The proportion of exclusion tests has gradually decreased after the introduction of direct CAG repeat testing, but the actual number of yearly intentional exclusion tests has remained fairly stable at three to four exclusion tests per year (Fig. 1b). Before 1993, when only linkage testing was available, the number of exclusion tests performed was relatively high. In the period from 1988 to 1998, in four cases, exclusion testing was the only technical option, because the haplotypes were uninformative, or there were not enough family members available [5] while only 13 out of 17 couples (76%) intentionally opted for exclusion testing as they did not want to know the HD expansion status of the at-risk parent. Taking this overestimation into account, we can see an even stronger stability of the absolute number of couples requesting exclusion testing.


Figure 1. (a) Prenatal tests for Huntington's disease in the Netherlands (1988–2008). In (a) and (b) the figures until 1997 are derived from Ref. [5], completed with the current data until 2008. (b) Exclusion and direct prenatal tests for HD in the Netherlands (1988–2008). In the period up to 1997, the exclusion-definitive tests (n=) were counted together with the exclusion tests.

Download figure to PowerPoint

Uptake of PND

We estimated the uptake of PND among carriers of an expanded repeat. The HD status of the 103 at-risk persons (Table 3) was (directly or indirectly) disclosed on average 2.2 years before their first PND test (range 14.41 years before to 9.07 years after PND). From this, we concluded that the 11-year period starting October 1996 was the closest way to establish the timing of PT in our study population. In this period 1414 PT were performed, in which 962 individuals were at reproductive age at the moment of PT and 406 showed a CAG repeat ≥36 (199 males <50 years and 207 females <40 years). Additionally, three untested individuals of reproductive age turned out to be HD expansion carriers after an unfavourable outcome of exclusion-definitive testing or direct PND, resulting in a total of 409 HD expansion carriers. Four out of the 93 carriers of an HD expansion ≥36 (Table 3) were excluded because they had had PT performed abroad or had been tested diagnostically. This leads to an estimated uptake of PND of 22% (89/409) among HD expansion carriers. The age at PT of males and females not opting for PND was significantly higher (34.3 and 29.4, respectively), compared with the age at PT of couples opting for PND (males 31.0 and females 27.0) (age differences: males p = 0.02; females p = 0.001).


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

In the 11 years from 1998 to 2008 a total of 126 couples underwent 216 prenatal tests in the Netherlands. Most couples opt for a direct test. The proportion of couples opting for an exclusion test has decreased from about 25% in the period 1987–1997 [5] to 13.5% in this study. The proportion of exclusion testing PND vs direct testing varied from around 30% in Australia (1994–2003) [11], to about 10% in Belgium, 29% in France, 30% in Denmark, 42% in Italy and 48% in UK (1993–1998) [12-14]. In Germany, Switzerland, Austria, and Greece no exclusion tests were performed (1993–1998) [14-16]. The absolute number of Dutch couples requesting exclusion tests over the years, even since the availability of direct testing, has remained quite stable. One might conclude that for a subgroup of at-risk individuals this is an attractive option. Apparently, these couples prefer the risk of terminating a non-affected foetus over disclosure of their own HD status. The motives of couples opting for exclusion testing are described elsewhere [17].

The intermediate alleles found in 4% of direct PND tests (8/189 including four exclusion-definitive tests) may be considered a background/population risk. In most foetuses (6/8), the origin was clearly different from the HD-causing allele, and in the remaining two (27 and 28 CAG repeats, respectively) it seems unlikely that these alleles are the ones causing HD in a close relative. In the Western European population, the background prevalence of intermediate alleles (27–35 CAG repeats) is estimated at around 2–6% [18-20].

Compared with Maat-Kievit et al. [5], two new subgroups of PND applicants appeared. First, carriers of an intermediate allele represented 4% of individuals requesting PND. After receiving their ‘grey’ PT result [10], the main reason to perform PND was to eradicate HD completely. To our knowledge, PND has not been described before for intermediate alleles. However, Decruyenaere et al. described one PND test in a woman with an equivocal repeat size (27–39 repeats) which was continued because the number of CAG repeats, the exact sizes of which were not mentioned [21], was lower than 40. The chance of intermediate alleles expanding into a reduced penetrance allele or very rarely into the full penetrance allele ranges from 1% to 20% of transmissions [19, 21-25]. Expansion risk is associated with a longer repeat length of the at-risk parent and mainly with paternal transmission.

Second, individuals at 50% HD risk opting for direct PND (25% prior risk for the foetus) represented about 8% of PND applicants [5]. This group represented 5% in a UK study and 37.5% in Germany, Austria and Switzerland [12, 15]. For individuals who object to terminating a 50% risk pregnancy but do accept the 25% chance of disclosure of their own HD status, this could be a valid alternative [5]. This method may also be applied to save time [compared with the time frame needed for successive PT and PND (or exclusion-definitive testing)] if couples do not present themselves until during the pregnancy [26]. The main disadvantage is the chance of ‘double bad news’ should the foetus turn out to carry the CAG expansion, and indirectly confirms its at-risk parent's HD status [5, 27, 28].

The majority of CAG expansion or 50% risk pregnancies was terminated; however, a substantial 13% were continued to term. According to international guidelines, continuing an CAG expansion or at-risk pregnancy of a late-onset disorder like HD can be considered an early form of predictive testing and therefore violates the future child's right not to know [8, 28, 29]. In the study period 1987–1997, all HD positive and high risk pregnancies (n = 28) were terminated. Continuation of a pregnancy with a CAG expansion or 50% HD risk has been described previously [13, 15, 30-32]. One may speculate about the risk factors making the decision to terminate such a pregnancy difficult. For some couples, the ‘double bad news’ of an HD test result in a 25% prior risk pregnancy might have complicated the decision to terminate the affected pregnancy. Furthermore, a reduced penetrance allele in a foetus may induce a sense of hope despite the disappointing test results as a whole. Individuals at risk of transmitting HD to their offspring do show a tendency to hold on to objectively rather small levels of hope as part of their coping strategy [33-35]. The observation that some couples do eventually continue a pregnancy with a smaller CAG repeat than their own – yet still a full penetrance allele – supports this idea. Therefore, if couples are determined to eradicate HD from their family, and if they expect difficulties to terminate when knowing the exact repeat length, especially in a certain range, they might prefer not to know the exact repeat size. These couples can agree with the counsellor to set a specific cut-off CAG repeat level, above which a ‘HD carrier’ result will be communicated. Naturally, the exact way of communicating the test result should be thoroughly discussed with each couple prior to the PND test. In individual cases, this form of non-disclosure of the exact CAG repeat size may reduce the reluctance of parents to terminate a pregnancy. According to Dutch law, parents are entitled to receive test results in full [36]. Moreover, a reproductive history of miscarriages or pregnancy terminations, as well as the presence of untested children within the same family, may increase parents' reluctance to terminate another pregnancy. Confronted with an HD positive or 50% risk result, the couple may have the complex association of rejecting an already existing child or the at-risk parent when opting for a termination of the pregnancy [37]. Furthermore, the time transpiring between PND intake and test result may affect couples' moral judgement on the acceptability of TOP [38]. The motives of these couples and the long-term consequences of this unfavourable outcome after PND will be the subject of future study.

Compared with the period studied by Maat et al. (1987–1997) [5], the number of 92 prenatal tests in the Netherlands has more than doubled to 216. A similar twofold increase (11–22%) was observed in the approximated uptake of PND by HD expansion carriers [5]. We assume that the uptake estimate in the study of Maat-Kievit et al. showed an underestimation of the actual uptake of PND because of the reported time lapse of 19 months between PT and first PND, as was reflected in the bar charts of PT applicants and prenatal tests in the Netherlands (1987–1997) [5, 39]. The uptake of PND among PT applicants with reproductive motives, in our study and in the previous study period, may be even higher; however, these motives were not centrally collected.

As PGD can be regarded as an alternative to PND it is interesting to note that after the introduction of PGD for HD in the Netherlands in 1999, the use of PND in terms of absolute figures did not decline (van Rij et al. submitted). In contrast, in France PND is only rarely performed after the introduction of PGD [8].

The uptake of PND by HD expansion carriers in the Netherlands is relatively high compared with France, Canada, the United States, Germany, Austria, Switzerland, Greece, Australia, and Northern-Ireland [8, 11, 14, 16, 26, 40-42] but is roughly comparable with UK, South Africa (Johannesburg), Belgium, and Denmark [12-14, 31, 43]. Since 2010, PND for HD has been prohibited in Germany; prenatal testing and termination of a pregnancy for HD are considered a form of genetic discrimination because of the late onset of HD [44]. In our study, the motives for performing a PT were not registered systematically; therefore, we assume that the actual uptake among individuals with reproductive motives for PT will most probably be higher. Additional support for this idea is presented in another paper in the uptake of PND and PGD in the Netherlands (van Rij et al. simultaneously submitted article).

Difficulties in calculating the absolute uptake of PT with respect to the at-50% HD-risk population complicate an accurate calculation and comparison of the uptake between these populations [42, 45].

Implications for good practise

Reproductive counselling issues should be discussed according to the international guidelines [28]. Parents opting for PND should be aware that they are expected to terminate a pregnancy should the foetus show a CAG repeat expansion associated with HD. Sequential use of PND does not imply a moral obligation to use PND in future pregnancies. The willingness and ability of couples to undergo (another) pregnancy termination should be discussed in every single PND intake. Hesitation, at any time during the procedure, should be taken seriously. Couples should be given the opportunity to withdraw from PND at any time, preferably before performing chorionic villus sampling, or at the latest before receiving the PND result.

In some cases non-disclosure of the exact CAG repeat size may reduce the reluctance of parents to terminate an affected pregnancy; this should be discussed prior to PND. Alternative reproductive options such as PGD should be considered during reproductive counselling.


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

The use of PND for HD in the Netherlands for both direct testing and exclusion has remained reasonably stable over the years. PND was used by two new subgroups: carriers of intermediate alleles, and couples opting for direct testing for a 25% HD risk for the foetus. A considerable number of affected or at-risk pregnancies were continued, for which we identified some risk factors. Couples' willingness to undergo TOP on account of HD should be explored thoroughly prior to and during the PND procedure.


  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References
  • 1
    Bates G, Harper P, Jones L, (eds). Huntington's disease. New York, NY: Oxford University Press, 2002.
  • 2
    Gusella JF, Wexler NS, Conneally PM et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 1983: 306: 234238.
  • 3
    Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993: 72: 971983.
  • 4
    Harper PS, Sarfarazi M. Genetic prediction and family structure in Huntington's chorea. Br Med JClinical research ed 1985: 290: 19291931.
  • 5
    Maat-Kievit A, Vegter-van der Vlis M, Zoeteweij M et al. Experience in prenatal testing for Huntington's disease in The Netherlands: procedures, results and guidelines (1987–1997). Prenat Diagn 1999: 19: 450457.
  • 6
    Moutou C, Gardes N, Viville S. New tools for pre-implantation genetic diagnosis of Huntington's disease and their clinical applications. Eur J Hum Genet 2004: 12: 10071014.
  • 7
    Sermon K, De Rijcke M, Lissens W et al. Preimplantation genetic diagnosis for Huntington's disease with exclusion testing. Eur J Hum Genet 2002: 10: 591598.
  • 8
    Van Rij MC, De Rademaeker M, Moutou C et al. Preimplantation genetic diagnosis (PGD) for Huntington's disease: the experience of three European centres. Eur J Hum Genet 2012: 20: 368375.
  • 9
    Dreesen J, Drusedau M, Smeets H et al. Validation of pre-implantation genetic diagnosis by PCR analysis: genotype comparison of the blastomere and corresponding embryo, implications for clinical practice. Mol Hum Reprod 2008: 14: 573579.
  • 10
    Semaka A, Balneaves LG, Hayden MR. “Grasping the Grey”: patient understanding and interpretation of an intermediate allele predictive test result for Huntington disease. J Genet Couns 2012: [Epub ahead of print].
  • 11
    Tassicker RJ, Marshall PK, Liebeck TA, Keville MA, Singaram BM, Richards FH. Predictive and pre-natal testing for Huntington Disease in Australia: results and challenges encountered during a 10-year period (1994–2003). Clin Genet 2006: 70: 480489.
  • 12
    Simpson SA, Harper PS. Prenatal testing for Huntington's disease: experience within the UK 1994–1998. J Med Genet 2001: 38: 333335.
  • 13
    Simpson SA, Zoeteweij MW, Nys K et al. Prenatal testing for Huntington's disease: a European collaborative study. Eur J Hum Genet 2002: 10: 689693.
  • 14
    Yapijakis C, Laccone F, Sorensen SA. Predictive and prenatal testing for Huntington's disease in Greece, Germany, Austria, Switzerland and Denmark. In: Evers-Kiebooms G, ed. Prenatal testing for late-onset neurogenetic diseases. Oxford: BIOS Scientific Publishers Ltd, 2002: 6982.
  • 15
    Laccone F, Engel U, Holinski-Feder E et al. DNA analysis of Huntington's disease: five years of experience in Germany, Austria, and Switzerland. Neurology 1999: 53: 801806.
  • 16
    Panas M, Karadima G, Vassos E et al. Huntington's disease in Greece: the experience of 14 years. Clin Genet 2011: 80: 586590.
  • 17
    van Rij MC, de Die-Smulders CE, Bijlsma EK et al. Evaluation of exclusion prenatal and exclusion pre-implantation genetic diagnosis for Huntington's disease in the Netherlands. Clin Genet 2012: [Epub ahead of print].
  • 18
    Maat-Kievit A, Losekoot M, Van Den Boer-Van Den Berg H et al. New problems in testing for Huntington's disease: the issue of intermediate and reduced penetrance alleles. J Med Genet 2001: 38: E12.
  • 19
    Semaka A, Collins JA, Hayden MR. Unstable familial transmissions of Huntington disease alleles with 27–35 CAG repeats (intermediate alleles). Am J Med Genet B Neuropsychiatr Genet 2010: 153B: 314320.
  • 20
    Sequeiros J, Ramos EM, Cerqueira J et al. Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population. Clin Genet 2010: 78: 381387.
  • 21
    Goldberg YP, McMurray CT, Zeisler J et al. Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population. Hum Mol Genet 1995: 4: 19111918.
  • 22
    Wheeler VC, Persichetti F, McNeil SM et al. Factors associated with HD CAG repeat instability in Huntington disease. J Med Genet 2007: 44: 695701.
  • 23
    Semaka A, Creighton S, Warby S, Hayden MR. Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Clin Genet 2006: 70: 283294.
  • 24
    Chong SS, Almqvist E, Telenius H et al. Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses. Hum Mol Genet 1997: 6: 301309.
  • 25
    Brocklebank D, Gayan J, Andresen JM et al. Repeat instability in the 27–39 CAG range of the HD gene in the Venezuelan kindreds: counseling implications. Am J Med Genet B Neuropsychiatr Genet 2009: 150B: 425429.
  • 26
    Richards FH, Rea G. Reproductive decision making before and after predictive testing for Huntington's disease: an Australian perspective. Clin Genet 2005: 67: 404411.
  • 27
    IHA-WFN. International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease. J Med Genet 1994: 31: 555559.
  • 28
    Macleod R, Tibben A, Frontali M et al. Recommendations for the predictive genetic test in Huntington's disease. Clin Genet 2012: [Epub ahead of print].
  • 29
    Toufexis M, Gieron-Korthals M. Early testing for Huntington disease in children: pros and cons. J Child Neurol 2010: 25: 482484.
  • 30
    Creighton S, Almqvist EW, MacGregor D et al. Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000. Clin Genet 2003: 63: 462475.
  • 31
    Decruyenaere M, Evers-Kiebooms G, Boogaerts A et al. The complexity of reproductive decision-making in asymptomatic carriers of the Huntington mutation. Eur J Hum Genet 2007: 15: 453462.
  • 32
    Tolmie JL, Davidson HR, May HM, McIntosh K, Paterson JS, Smith B. The prenatal exclusion test for Huntington's disease: experience in the west of Scotland, 1986–1993. J Med Genet 1995: 32: 97101.
  • 33
    Quaid KA, Sims SL, Swenson MM et al. Living at risk: concealing risk and preserving hope in Huntington disease. J Genet Couns 2008: 17: 117128.
  • 34
    Bombard Y, Penziner E, Decolongon J et al. Managing genetic discrimination: strategies used by individuals found to have the Huntington disease mutation. Clin Genet 2007: 71: 220231.
  • 35
    Quaid KA, Swenson MM, Sims SL et al. What were you thinking?: individuals at risk for Huntington disease talk about having children. J Genet Couns 2010: 19: 606617.
  • 36
    Wet Geneeskundige Behandel Overeenkomst, Dutch Civil Law, BW Art. 7:458. 2011.
  • 37
    Richards M. Predictive testing for Huntington's disease. Lancet 2001: 357: 883.
  • 38
    Scully JL, Porz R, Rehmann-Sutter C. ‘You don't make genetic test decisions from one day to the next’--using time to preserve moral space. Bioethics 2007: 21: 208217.
  • 39
    Maat-Kievit A, Vegter-van der Vlis M, Zoeteweij M, Losekoot M, van Haeringen A, Roos R. Paradox of a better test for Huntington's disease. J Neurol Neurosurg Psychiatry 2000: 69: 579583.
  • 40
    Nance MA. Predictive and prenatal testing for late-onset neurogenetic diseases in North-America. In: Evers-Kiebooms G, Zoeteweij MW, Harper PS, eds. Prenatal testing for late-onset neurogenetic diseases. Oxford: BIOS Scientific Publishers Ltd, 2002: 191201.
  • 41
    Dufrasne S, Roy M, Galvez M, Rosenblatt DS. Experience over fifteen years with a protocol for predictive testing for Huntington disease. Mol Genet Metab 2011: 102: 494504.
  • 42
    Morrison PJ, Harding-Lester S, Bradley A. Uptake of Huntington disease predictive testing in a complete population. Clin Genet 2011: 80: 281286.
  • 43
    Sizer EB, Haw T, Wessels TM, Kromberg JG, Krause A. The utilization and outcome of diagnostic, predictive, and prenatal genetic testing for Huntington disease in Johannesburg, South Africa. Genet Test Mol Biomarkers 2012: 16: 5862.
  • 44
    Gesetz über genetische Untersuchungen beim Menschen (Regulation on genetic testing in humans). Art. 74 Abs. 1 Nr. 26 GG. Germany, 2009.
  • 45
    Tassicker RJ, Teltscher B, Trembath MK et al. Problems assessing uptake of Huntington disease predictive testing and a proposed solution. Eur J Hum Genet 2009: 17: 6670.