Preimplantation diagnosis for Huntington's disease (HD): clinical application and analysis of the HD expansion in affected embryos

Abstract

Huntington's disease (HD) is an autosomal dominant disease characterized by motor disturbance, cognitive loss and psychiatric manifestations, starting between the fourth and the fifth decade, followed by death within 10–20 years of onset of the disease. The disease‐causing mutation is an expansion of a CAG triplet repeat at the 5′ coding end of the Huntington gene. We have developed a single‐cell PCR assay for the HD gene in order to propose preimplantation genetic diagnosis (PGD) for the couples at risk. We present here our first results with our first nine PGD cycles and also discuss the behaviour of the disease‐causing expansion in pre‐implantation embryos. Copyright © 1998 John Wiley & Sons, Ltd.

New tools for preimplantation genetic diagnosis of Huntington's disease and their clinical applications

“…10 For group I patients, we used a simplex PCR amplifying the CAG repeats. 5 The drawback of this test comes from the difficulty of amplifying the long repeats, meaning that the couple has to carry nonpathological CAG repeats of different sizes. Therefore, in a first instance, we determine the haplotype of the CAG repeat of both members of the couple and, if they are fully informative, we use this test.…”

“…2 -4 For at-risk persons who know or do not know their genetic status and wish to create a family, this question becomes even more stringent and different options are now available. Indeed, besides adoption or gamete donation, they can opt for prenatal diagnosis (PND) with possible termination of pregnancy (TOP) or preimplantation genetic diagnosis (PGD) 5 with selective uterine transfer of unaffected embryos.…”

Preimplantation genetic diagnosis for Huntington's disease with exclusion testing

“…3 This means that only embryos containing seven cells or more on the morning of day three are considered suitable for biopsy. A noncontact, 1.48 mm diode laser system (Fertilase, MTM Medical Technologies Montreux, Switserland) was used to create a funnel-shaped hole in the zona pellucida.…”

“…2 We have described PGD for HD based on the enzymatic amplification of the CAG triplet repeat causing the mutation 1 and have applied this test in 16 couples in whom one of the partners was known to carry the expanded allele after presymptomatic testing. 3 It has been suggested 4 that this test might also be used for patients who do not wish to know their carrier status, in which case it would be termed non-disclosure, to differentiate it from exclusion testing. One centre has applied this test with apparently good results: 5 embryos are analysed before implantation without revealing to the patient any detail of the course of the IVF/ICSI cycle, after which only embryos without the expansion are transferred.…”

“…Finally, a mock-transfer would have to be performed if no embryos were available for transfer, lest the patient would draw the conclusion that he or she was indeed a carrier. 3,6 Exclusion prenatal testing, in which a foetus is checked for the presence of an allele from the affected grandparent was described as early as 1987, 7 initially to avoid the birth of offspring at risk to persons at risk for whom definitive testing was not possible. The most important drawback of this method is that unaffected foetuses may be terminated.…”