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Hum. Reprod. Advance Access published online on May 31, 2006
Human Reproduction, doi:10.1093/humrep/del064
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 2, 2005
Revised February 7, 2006
Accepted February 10, 2006

Article

Single-sperm analysis for haplotype construction of de-novo paternal mutations: application to PGD for neurofibromatosis type 1

G. Altarescu 1, B. Brooks 2, Y. Kaplan 1, T. Eldar-Geva 2, E.J. Margalioth 2, E. Levy-Lahad 3, and P. Renbaum 4 *

1 Medical Genetics Unit, Jerusalem, Israel
2 IVF Unit, Zohar PGD Laboratory Shaare Zedek Medical Center, Jerusalem, Israel
3 Medical Genetics Unit; Hebrew University-Hadassah Medical School, Jerusalem, Israel
4 Medical Genetics Unit, Shaare Zedek Medical Center, Jerusalem 91031, Israel

* To whom correspondence should be addressed.
P. Renbaum, E-mail: renbaum{at}szmc.org.il


  Abstract

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the neurofibromin gene. Approximately, 50% of cases are caused by de-novo mutations. Even when the NF1 mutation is known, accuracy of PGD is highly enhanced by simultaneous analysis of linked markers. In a childless couple referred to PGD, the male carried a de-novo mutation, precluding the possibility of typing relatives to establish the mutation-associated haplotype. We developed a single-sperm haplotype analysis strategy to establish the haplotype linked to the NF1 mutation. METHODS: Spermatozoa from freshly ejaculated semen were used as a substrate for multiplex PCR on single sperm. RESULTS: In addition to the NF1 mutation, six informative polymorphic markers flanking the NF1 gene (D17S1294, D17S1849, D17S841, D17S975, NF1TG2 and NF1AC5) were linked to individual alleles in single sperm from the affected male. CONCLUSIONS: Single-sperm analysis established the haplotypes of both mutant and wild-type NF1 alleles and enabled the implementation of a PGD protocol using polymorphic marker analysis. This method is generally applicable to PGD for any disease in which the haplotype of paternal mutations cannot be determined by typing relatives.

Keywords: single-sperm PCR/NF1/PGD/polymorphic markers.
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G. Altarescu, T. Eldar-Geva, I. Varshower, B. Brooks, E. Z. Haran, E. J. Margalioth, E. Levy-Lahad, and P. Renbaum
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