Preimplantation diagnosis for neurofibromatosis

Abstract

Preimplantation genetic diagnosis (PGD) has recently been performed for inherited cancer predisposition determined by p53 tumour suppressor gene mutations, suggesting the usefulness of PGD for late onset disorders with genetic predisposition, including those caused by the germline mutations of other tumour suppressor genes. Here PGD was performed for two couples, one at risk for producing a child with maternally derived neurofibromatosis type I (NF1), and the other with paternally derived neurofibromatosis type II (NF2). The procedure involved a standard IVF protocol, combined with testing of oocytes or embryos prior to their transfer back to the patients. Maternal mutation Trp-->Ter (TGG-->TGA) in exon 29 of the NF1 gene was tested by sequential PCR analysis of the first and second polar bodies, and paternal L141P mutation in exon 4 of the NF2 gene by embryo biopsy at the cleavage stage. In both cases, multiplex nested PCR was applied, involving NF1 and NF2 mutation analysis simultaneously with the 3 and 2 linked markers, respectively. Of 57 oocytes tested in four PGD cycles for NF1 mutation, 26 mutation-free oocytes were detected, from which eight were preselected for transfer, two in each cycle. These produced two clinical pregnancies, one confirmed to be mutation free by chorionic villus sampling but ending in a stillbirth, and the other still ongoing. Of 18 embryos analysed in a cycle performed for NF2 mutation, eight mutation-free embryos were detected, three of which were transferred back to the patient, resulting in a singleton pregnancy and the birth of a mutation-free child. This suggests that PGD is a useful approach for avoiding the birth of children with inherited cancer predisposition, determined by NF1 and NF2 gene mutations.

Neurofibromatosis 1

“…Preimplantation diagnosis may be useful for a couple at risk for having a child with Nf1 and has been introduced in some centres. 12 (1) Differential diagnosis. (2) The major differential diagnoses of Nf1 are described in Table 2 13 Clinicians should be aware of individuals with segmental/mosaic Nf1 who present with six or more cafe´au lait patches and skin-fold freckling in the affected area.…”

Outcomes of preimplantation genetic diagnosis in neurofibromatosis type 1

“…Previous publications have documented aggregate outcomes of PGD for multiple monogenic diseases (10,13,14,15,16) and prior NF1-specific reports have been case series of a small number of patients. (17,18,19) For this reason, we retrospectively evaluated the diagnostic and clinical outcomes for couples affected by NF1 who pursued PGD at a large international laboratory that provides PGD services.…”

Molecular diagnosis of neurofibromatosis type 1: 2 years experience

“…As a result, there has been little demand to date for prenatal diagnosis, possibly because most couples would want to know the clinical severity of the disease in their baby, which currently cannot be predicted [8]. Despite this lack of demand, there is still an urgent need for a cost-effective, rapid and accurate DNA-based test for NF1, and development of a suitable preimplantation test for NF1 has been reported [15,16].…”